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Paik, Daniel H., and Donna L. Farber. "Lung tissue resident memory T cells coordinate effector T cell dynamics during the protective recall response to influenza." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 173.7. http://dx.doi.org/10.4049/jimmunol.200.supp.173.7.
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Abstract Influenza remains a serious public health challenge as the current vaccination strategy cannot protect against new strains that emerge every season. Tissue resident memory T cells (TRM) are a non-circulating memory subset that are generated in the lung after influenza infection or intranasal live vaccination, and these lung TRM have been shown to confer broad cross-strain protection. However, the mechanisms by which both CD4+ and CD8+ TRM mediate their protective response are not well defined. We investigated the tissue specific events during an active murine influenza response, including TRM-mediated protection and effector T cell trafficking. To specifically determine the role of TRM, we treated mice with the drug Fingolimod (FTY720), which sequesters circulating lymphocytes into secondary lymphoid organs, enriching the lung for tissue resident memory cells. We found that TRM immediately confer protection, with reduced viral titers evident as early as day 3 after infection. At later time points beginning at days 4–5 post infection, we determined that CD4+ and CD8+ TRM enhance the recruitment of influenza-specific effector T cells into the lung resident niche as well as CD4+ and CD8+ lymphocyte in situ proliferation as measured by BrdU incorporation. Furthermore, total lung RNA sequencing during active infection and FTY720 treatment reveal candidate TRM-associated chemokine pathways for tissue lymphocyte trafficking. These findings indicate that TRM uniquely influence the cellular dynamics of the lung resident niche to mediate cross-strain protection against influenza.
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Cullen, Jolie G., Moshe Olshansky, and Stephen Turner. "The molecular basis of CD4+ T cell priming for CD8+ T cell memory formation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 129.2. http://dx.doi.org/10.4049/jimmunol.196.supp.129.2.
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Abstract A long-lived pool of potent memory cells is the defining feature of adaptive immunity. Memory CD8 T cells offer protection for the life of the host due to their unique capabilities to survive in the absence of antigen and respond rapidly to secondary challenge. Therefore, effective CD8 T cell memory is the goal of cell-mediated vaccination strategies. While it is well established that CD4 help is required for CD8 T cell memory formation, it is unclear when during CD8 differentiation this help is required. Further, the affect that CD4 help has on the transcriptional profiles of CD8 T cells and the molecular pathways they use during the generation and maintenance of memory CD8 T cells remains elusive. Using a mouse model of Influenza A virus infection, where priming occurs in the presence or absence of CD4 T cell help, we have pinpointed that help is required during the initial priming of CD8 T cells, and not during memory maintenance or recall. Genome wide RNA-sequencing analysis of the transcriptional signatures between resting “helped” and “ unhelped” memory CD8 T cells reveals surprisingly few differentially expressed genes. However, upon reactivation, “helped” memory CD8 T cells exhibited greater transcriptional up regulation than their “unhelped” counterparts, and utilization of alternate molecular pathways. Our analysis revealed that CD4 help during initial priming is essential for establishing a memory cell pool with enhanced transcriptional potential. Intriguing metabolism differences are currently being further dissected based on this RNA-sequencing data. Thus, CD4 T cell dependent programming likely underpins rapid responsiveness, a key characteristic of memory CD8 T cells.
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Xiao, Minglu, Luoyingzi Xie, Guoshuai Cao, Shun Lei, Pengcheng Wang, Zhengping Wei, Yuan Luo, et al. "CD4+ T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy." Journal for ImmunoTherapy of Cancer 10, no. 5 (May 2022): e004022. http://dx.doi.org/10.1136/jitc-2021-004022.
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BackgroundAntitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8+ T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from tumor-derived CD8+ T-cell epitopes can drive the functional exhaustion of tumor-specific CD8+ T cells. Tumor-specific type-I helper CD4+ T (TH1) cells play an important role in the population maintenance and cytotoxic function of exhausted tumor-specific CD8+ T cells in the tumor microenvironment. Nonetheless, whether the vaccination strategy targeting MHC-II-restricted CD4+ T-cell epitopes to induce tumor-specific TH1 responses can confer effective antitumor immunity to restrain tumor growth is not well studied. Here, we developed a heterologous prime-boost vaccination strategy to effectively induce tumor-specific TH1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1/PD-L1 immunotherapy.MethodsListeria monocytogenes vector and influenza A virus (PR8 strain) vector stably expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein-specific I-Ab-restricted CD4+ T cell epitope (GP61–80) or ovalbumin-specific CD4+ T cell epitope (OVA323-339) were constructed and evaluated their efficacy against mouse models of melanoma and colorectal adenocarcinoma expressing lymphocytic choriomeningitis virus glycoprotein and ovalbumin. The impact of CD4+ T cell epitope-based heterologous prime-boost vaccination was detected by flow-cytometer, single-cell RNA sequencing and single-cell TCR sequencing.ResultsCD4+ T cell epitope-based heterologous prime-boost vaccination efficiently suppressed both mouse melanoma and colorectal adenocarcinoma. This vaccination primarily induced tumor-specific TH1 response, which in turn enhanced the expansion, effector function and clonal breadth of tumor-specific CD8+ T cells. Furthermore, this vaccination strategy synergized PD-L1 blockade mediated tumor suppression. Notably, prime-boost vaccination extended the duration of PD-L1 blockade induced antitumor effects by preventing the re-exhaustion of tumor-specific CD8+ T cells.ConclusionCD4+ T cell epitope-based heterologous prime-boost vaccination elicited potent both tumor-specific TH1 and CTL response, leading to the efficient tumor control. This strategy can also potentiate PD-1/PD-L1 immune checkpoint blockade (ICB) against cancer.
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Matysiak, Colette, Samuel Kazer, Jose Ordovas-Montanes, and Ulrich H. von Andrian. "Intranasal, not parenteral, vaccination induces the formation of tissue-resident memory CD8 T cells in nasal mucosa that rapidly clear influenza virus infection." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 114.17. http://dx.doi.org/10.4049/jimmunol.208.supp.114.17.
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Abstract Respiratory tract infections are among the leading causes of death. While current vaccines reduce severe disease, they provide suboptimal mucosal protection (e.g. against influenza virus and SARS-CoV-2). Nasal vaccines offer an advantage by quickly limiting viral shedding, in part by generating tissue-resident memory (Trm) CD8 T cells in the nasal mucosa. But little is known about the molecular requirements for this Trm formation. The common paradigm is that lymphocytes home to tissues after having been imprinted within draining lymph nodes to express a tissue-specific combination of trafficking molecules, and Trm cells form rapidly from this pool. To probe the paradigm of tissue homing to the nasal mucosa, we compared CD8 T cell trafficking following intranasal and intramuscular vaccination. To investigate the trafficking molecules expressed by CD8 T cells and nasal cells we generated a single-cell RNA sequencing profile of the nasal mucosa over the course of an acute influenza infection. We found significantly more CD8 Trm cells in the nasal mucosa following intranasal vaccination that rapidly cleared influenza infection. Notably, CD8 T cells could be “pulled” into the nasal mucosa with an inflammatory stimulus following intramuscular vaccination, suggesting a new strategy for generating nasal CD8 Trm cells. Unlike canonical T cell homing to the gut and skin, nasal CD8 T cell trafficking depended on a4/VCAM1 (not a4b7/MADCAM1 or P and E-Selectin), and CD8 T cells expressed high levels of CXCR3 and CXCR6. This combination of trafficking molecules suggests a distinct multi-step adhesion cascade for CD8 T cell recruitment to the nasal mucosa and provides critical insights to rationally design vaccines for respiratory tract protection. Supported by grants from NIH (R01 AR068383-01, P01 AI 112521) and HMS-AbbVie Alliance
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Wierecky, Jan, Martin R. Müller, Maik Häntschel, Marius S. Horger, Steve Pascolo, Wolfram Brugger, Lothar Kanz, and Peter Brossart. "Intradermal RNA-Vaccination of Patients with Metastatic Renal Cell Carcinoma." Blood 106, no. 11 (November 16, 2005): 3881. http://dx.doi.org/10.1182/blood.v106.11.3881.3881.
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Abstract Background: The use of in vitro transcribed RNA isolated from tumor cells or coding for defined tumor associated antigens was shown to be a very powerfull method to generate antigen specific T cells upon transfection into dendritic cells (DC). More recently it was demonstrated in a mouse model that application of RNA intra dermaly can elicit both, CD8 and CD4 mediated immune responses. Furthermore, in Her-2-neu transgenic mice vaccinations with naked RNA were able to elicit a specific immune response in vivo and delay the development of breast cancer in treated animals. Based on these results we analyzed the clinical and immunological responses in patients with metastatic renal cell carcinoma (RCC) vaccinated with mRNA encoding for tumor associated antigens (TAA) using two different treatment arms. Methods: In vitro transcribed RNA was generated using plasmids coding for the tumor antigens MUC1, CEA, Her-2/neu, telomerase, survivin and MAGE-1. RNA coding for HbsAg and Influenza matrix protein were included as controls. Vaccinations were performed intradermally on day 1,14, 28 and 42 in a first group of patients and on day 0–3, 7–10, 28 and 42 in a second group (intensified arm). Vaccinations were repeated afterwards monthly until tumor progression. One day after each RNA injection patients additionally received 1 injection of GM-CSF (250 μg) sc. The enhancement of T cell precursor was monitored using IFN-g ELISPOT and tetramer staining.. Results: 25 patients were included in this study. In 3 patients regression of metastases was induced and 6 patients had a stabilization of the disease. Specific CD8 and CD4 T cell responses in vivo were detected in the first analyzed patients. The treatment was well tolerated with no severe side effects. In most cases erythema and induration were observed after injections of GM-CSF. One patient developed an allergic exanthema after GM-CSF application. Conclusions: This study demonstrates that intradermal RNA-vaccination can be effective in the treatment of metastatic RCC and induces clinical and immunological responses.
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Hong, David K., Stella Chang, Crystal M. Botham, Thierry D. Giffon, Jeffery Fairman, and David B. Lewis. "Cationic Lipid/DNA Complex-Adjuvanted Influenza A Virus Vaccination Induces Robust Cross-Protective Immunity." Journal of Virology 84, no. 24 (October 13, 2010): 12691–702. http://dx.doi.org/10.1128/jvi.00769-10.
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ABSTRACT Influenza A virus is a negative-strand segmented RNA virus in which antigenically distinct viral subtypes are defined by the hemagglutinin (HA) and neuraminidase (NA) major viral surface proteins. An ideal inactivated vaccine for influenza A virus would induce not only highly robust strain-specific humoral and T-cell immune responses but also cross-protective immunity in which an immune response to antigens from a particular viral subtype (e.g., H3N2) would protect against other viral subtypes (e.g., H1N1). Cross-protective immunity would help limit outbreaks from newly emerging antigenically novel strains. Here, we show in mice that the addition of cationic lipid/noncoding DNA complexes (CLDC) as adjuvant to whole inactivated influenza A virus vaccine induces significantly more robust adaptive immune responses both in quantity and quality than aluminum hydroxide (alum), which is currently the most widely used adjuvant in clinical human vaccination. CLDC-adjuvanted vaccine induced higher total influenza virus-specific IgG, particularly for the IgG2a/c subclass. Higher levels of multicytokine-producing influenza virus-specific CD4 and CD8 T cells were induced by CLDC-adjuvanted vaccine than with alum-adjuvanted vaccine. Importantly, CLDC-adjuvanted vaccine provided significant cross-protection from either a sublethal or lethal influenza A viral challenge with a different subtype than that used for vaccination. This superior cross-protection afforded by the CLDC adjuvant required CD8 T-cell recognition of viral peptides presented by classical major histocompatibility complex class I proteins. Together, these results suggest that CLDC has particular promise for vaccine strategies in which T cells play an important role and may offer new opportunities for more effective control of human influenza epidemics and pandemics by inactivated influenza virus vaccine.
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Magini, Diletta, Scilla Buccato, Simona Mangiavacchi, Cinzia Giovani, Emanuele Montomoli, Luis Brito, Domenico Maione, Andrew Geall, Michela Brazzoli, and Sylvie Bertholet. "Characterization of T cell responses induced by Flu SAM(NP)® and SAM(M1)® vaccines (VAC5P.1124)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 73.9. http://dx.doi.org/10.4049/jimmunol.194.supp.73.9.
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Abstract Vaccination remains the most cost-effective way to control Influenza outbreaks. However, current Influenza vaccines do not provide efficacious heterosubtypic immunity. Therefore, the development of a successful universal vaccination strategy is urgently needed. To achieve this goal, one approach is focused on the induction of a T cell based response versus more conserved flu antigens, such as the Nucleoprotein (NP) and the Matrix protein 1 (M1). The aim of this study was to evaluate the immunogenicity and protective efficacy conferred by conserved NP and M1 antigens expressed by a self-amplifying RNA-based vaccine (SAM(NP)® and SAM(M1)®). We demonstrate that SAM(NP)® and SAM(M1)® are immunogenic in Balb/c mice. SAM(NP)® formulation induced IFNγ+ and LAMP1+ NP-specific cytotoxic CD8+ T cells as well as multifunctional NP-specific CD4+ T cells. SAM(M1) ® elicited a robust polyfunctional CD4 T helper 1 response. Moreover, we show that SAM(NP)® and SAM(M1)® formulations, when administered separately or in combination, provided differential levels of protection against a lethal challenge with mouse-adapted A/PR/8/1934 (H1N1) Influenza virus. SAM(NP)® and SAM(M1)® formulation induced T cell immune responses, potent mediator of heterosubtypic immunity, therefore, they are promising antigens in the design of a cross-protective flu vaccine. Since the SAM® vaccine technology offers several advantages , it could potentially speed up the development of universal flu vaccine candidates.
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Milner, J. Justin, Clara Toma, Kyla Omilusik, Hong Nguyen, Bingfei Yu, Arnaud Delpoux, Tomomi Yoshida, et al. "Epigenetic targeting of Brd4 constrains CD8+ T cell differentiation during infection and cancer." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 138.6. http://dx.doi.org/10.4049/jimmunol.202.supp.138.6.
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Abstract Memory CD8+ T cells afford long-lived, durable protection against infection and malignancy. Despite the critical relevance of memory T cells to vaccination and immunotherapies, the transcriptional and epigenetic signals instructing memory T cell fate remain unclear. Here, we utilized a pooled RNA interference screen to evaluate the activity of transcription factors and chromatin modifiers governing memory T cell differentiation in vivo. The epigenetic ‘reader,’ Brd4 of the BET protein family, emerged as a top regulator of memory T cell differentiation. Through RNA interference, small molecule inhibition and inducible genetic deletion, we established a central role for Brd4 in mediating CD8+ T cell proliferation, differentiation and function during acute viral infection. Brd4 was required for optimal expression of fate-specifying transcription factors, and a deficiency of Brd4 activity resulted in diminished formation of effector memory and CD103+ tissue-resident memory CD8+ T cells. Given that BET inhibition has emerged as a powerful approach for suppressing tumor growth, we also evaluated how BET inhibition and Brd4-deficiency influence T cell activity during cancer. Brd4 was required for intratumoral accumulation and function of T cells in a mouse model of melanoma, and BET inhibition suppressed T cell-mediated control of tumor growth. However, epigenetic targeting of Brd4 constrained terminal differentiation of T cells within tumors, biasing tumor-resident T cells towards a reprogrammable TCF1-expressing phenotype. These studies establish a novel role for Brd4 in CD8+ T cell biology and provide insight for immunotherapy approaches designed to leverage the dynamic activity of CD8+ T cells in tumors.
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Hemann, Emily A., John B. Grigg, Courtney R. Wilkins, Megan Knoll, Shawn P. Iadonato, Kristin Bedard, Peter Probst, Yueh-Ming Loo, and Michael Gale. "A small-molecule RIG-I agonist functions to enhance vaccine protection against influenza A virus infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 76.1. http://dx.doi.org/10.4049/jimmunol.196.supp.76.1.
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Abstract Viral sensing by RIG-I and downstream activation of antiviral defenses along with the induction of innate immune cytokines is essential from protection against influenza A virus (IAV) infection. We have identified a novel, small-molecule RIG-I agonist, KIN1148, which binds and activates RIG-I to signal the activation of IRF3 and the innate immune response. We are developing this molecule as an adjuvant to enhance vaccination against pandemic H1N1 (pH1N1) IAV. Ex vivo treatment of dendritic cells with KIN1148 leads to their activation and maturation. We determined the ability of KIN1148 to enhance suboptimal IAV vaccine responses in vivo. Administration of KIN1148 leads enhanced protection during high dose pH1N1 infection following a single, intramuscular administration of KIN1148 with IAV vaccine. This increase in protection is accompanied by a significant reduction in virus titers, as well as lung pathology. Analysis of the immune response induced following vaccination with KIN1148 as well as challenge demonstrates an increase in chemoattractant cytokines, germinal center B cells, IAV-specific antibodies, and IAV-specific CD4 and CD8 T cells compared to vaccination alone, indicating the induction of a broad anti-IAV immune response. Together these results demonstrate that prophylactic drug targeting of the RIG-I pathway with a small molecule enhances vaccine protection and highlight the potential of KIN1148 to enhancing vaccines against RNA virus infection.
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Staprans, S. I., B. L. Hamilton, S. E. Follansbee, T. Elbeik, P. Barbosa, R. M. Grant, and M. B. Feinberg. "Activation of virus replication after vaccination of HIV-1-infected individuals." Journal of Experimental Medicine 182, no. 6 (December 1, 1995): 1727–37. http://dx.doi.org/10.1084/jem.182.6.1727.
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Little is known about the factors that govern the level of HIV-1 replication in infected individuals. Recent studies (using potent antiviral drugs) of the kinetics of HIV-1 replication in vivo have demonstrated that steady-state levels of viremia are sustained by continuous rounds of de novo infection and the associated rapid turnover of CD4+ T lymphocytes. However, no information is available concerning the biologic variables that determine the size of the pool of T cells that are susceptible to virus infection or the amount of virus produced from infected cells. Furthermore, it is not known whether all CD4+ T lymphocytes are equally susceptible to HIV-1 infection at a given time or whether the infection is focused on cells of a particular state of activation or antigenic specificity. Although HIV-1 replication in culture is known to be greatly facilitated by T cell activation, the ability of specific antigenic stimulation to augment HIV-1 replication in vivo has not been studied. We sought to determine whether vaccination of HIV-1-infected adults leads to activation of virus replication and the targeting of vaccine antigen-responsive T cells for virus infection and destruction. Should T cell activation resulting from exposure to environmental antigens prove to be an important determinant of the steady-state levels of HIV-1 replication in vivo and lead to the preferential loss of specific populations of CD4+ T lymphocytes, it would have significant implications for our understanding of and therapeutic strategies for HIV-1 disease. To begin to address these issues, HIV-1-infected individuals and uninfected controls were studied by measurement of immune responses to influenza antigens and quantitation of virion-associated plasma HIV-1 RNA levels at baseline and at intervals after immunization with the trivalent influenza vaccine. Influenza vaccination resulted in readily demonstrable but transient increases in plasma HIV-1 RNA levels, indicative of activation of viral replication, in HIV-1-infected individuals with preserved ability to immunologically respond to vaccine antigens. Activation of HIV-1 replication by vaccination was more often seen and of greater magnitude in individuals who displayed a T cell proliferative response to vaccine antigens at baseline and in those who mounted a significant serologic response after vaccination. The fold increase in viremia, as well as the rates of increase of HIV-1 in plasma after vaccination and rates of viral decline after peak viremia, were higher in individuals with higher CD4+ T cell counts.(ABSTRACT TRUNCATED AT 400 WORDS)
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Bang, Yoo-Jin, Yun-Hee Kim, Yu-Sun Lee, Jae-Yong Kim, Hyo-Jung Park, Hae-Li Ko, Sang-In Park, Kyung-Ah Hwang, Hun Kim, and Jae-Hwan Nam. "Development of inactivated subunit influenza vaccine endowing with IgA induction and protection against heterologous strain." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 245.11. http://dx.doi.org/10.4049/jimmunol.204.supp.245.11.
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Abstract Vaccination is known to be the best way to prevent and control seasonal influenza infections. Among the various available influenza vaccines, an inactivated vaccine shows improved protective effects associated with greater safety. However, since the influenza virus is continuously evolving, its response to inactivated vaccines becomes increasingly difficult to predict, leading to complete or partial loss of protection against the virus. In addition, immunogenicity is lower than other types and Th2-biased immune responses have been reported. In this study, we have investigated the role of the single-stranded RNA (ssRNA) adjuvant derived from the intergenic region of internal ribosome entry site of Cricket Paralysis virus in seasonal inactivated subunit influenza vaccine (ISIV). We found that the ssRNA adjuvant stimulated balanced cellular (indicated by IgG2a, IFN-γ, IL-2, and TNF-α) and humoral (indicated by IgG1 and HI) responses, along with mucosal (indicated by IgA) immune response. Moreover, the ssRNA adjuvant formulated ISIV enhanced viral clearance and improved lung pathology after homologous and even heterologous influenza virus infections. The proportion of memory CD4+ and CD8+ T cells, important for long term immunity, was also observed to increase. Therefore, the ssRNA adjuvant formulated ISIV is effective in inducing humoral and cellular immune responses, cross protection, and long-term immunity.
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Beljanski, Vladimir, Cindy Chiang, Greg A. Kirchenbaum, David Olagnier, Chalise E. Bloom, Terianne Wong, Elias K. Haddad, Lydie Trautmann, Ted M. Ross, and John Hiscott. "Enhanced Influenza Virus-Like Particle Vaccination with a Structurally Optimized RIG-I Agonist as Adjuvant." Journal of Virology 89, no. 20 (August 12, 2015): 10612–24. http://dx.doi.org/10.1128/jvi.01526-15.
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ABSTRACTThe molecular interaction between viral RNA and the cytosolic sensor RIG-I represents the initial trigger in the development of an effective immune response against infection with RNA viruses, resulting in innate immune activation and subsequent induction of adaptive responses. In the present study, the adjuvant properties of a sequence-optimized 5′-triphosphate-containing RNA (5′pppRNA) RIG-I agonist (termed M8) were examined in combination with influenza virus-like particles (VLP) (M8-VLP) expressing H5N1 influenza virus hemagglutinin (HA) and neuraminidase (NA) as immunogens. In combination with VLP, M8 increased the antibody response to VLP immunization, provided VLP antigen sparing, and protected mice from a lethal challenge with H5N1 influenza virus. M8-VLP immunization also led to long-term protective responses against influenza virus infection in mice. M8 adjuvantation of VLP increased endpoint and antibody titers and inhibited influenza virus replication in lungs compared with approved or experimental adjuvants alum, AddaVax, and poly(I·C). Uniquely, immunization with M8-VLP stimulated a TH1-biased CD4 T cell response, as determined by increased TH1 cytokine levels in CD4 T cells and increased IgG2 levels in sera. Collectively, these data demonstrate that a sequence-optimized, RIG-I-specific agonist is a potent adjuvant that can be utilized to increase the efficacy of influenza VLP vaccination and dramatically improve humoral and cellular mediated protective responses against influenza virus challenge.IMPORTANCEThe development of novel adjuvants to increase vaccine immunogenicity is an important goal that seeks to improve vaccine efficacy and ultimately prevent infections that endanger human health. This proof-of-principle study investigated the adjuvant properties of a sequence-optimized 5′pppRNA agonist (M8) with enhanced capacity to stimulate antiviral and inflammatory gene networks using influenza virus-like particles (VLP) expressing HA and NA as immunogens. Vaccination with VLP in combination with M8 increased anti-influenza virus antibody titers and protected animals from lethal influenza virus challenge, highlighting the potential clinical use of M8 as an adjuvant in vaccine development. Altogether, the results describe a novel immunostimulatory agonist targeted to the cytosolic RIG-I sensor as an attractive vaccine adjuvant candidate that can be used to increase vaccine efficacy, a pressing issue in children and the elderly population.
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Hemann, Emily, Jae-Min Song, Sang-Moo Kang, and Kevin Legge. "Influenza virus-like particle vaccination boosts CD8 T cell immunity (113.28)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 113.28. http://dx.doi.org/10.4049/jimmunol.188.supp.113.28.
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Abstract Influenza virus-like particles (VLPs) have been demonstrated to provide protection against lethal influenza A virus (IAV) infections in mice following a single, intranasal (i.n.) vaccination. Previous work has demonstrated that VLP administration leads to an increase in virus-specific IgG production. However, the effect of VLP vaccination on the influenza-specific CD8 T cell response remains unknown. Given the important role of CD8 T cells in viral clearance, we determined the role of vaccine-induced CD8 T cell immunity in influenza VLP-mediated protection. Our results demonstrate that the HA533-specific CD8 T cell response is significantly boosted in the lungs, spleens and lung-draining lymph nodes of VLP-vaccinated mice following IAV challenge. Further, adoptive transfer of CL4 (HA533-specific) T cells and serum from VLP-vaccinated mice improved mortality following lethal infection compared to transfer of T cells or serum alone. Together, our results suggest that memory CD8 T cell responses contribute to the protection mediated by influenza VLP vaccination and support the potential use of VLPs as an effective influenza vaccine candidate.
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Kaczmarek, Radoslaw, Thais Bertolini, and Roland W. Herzog. "Revisiting the "Danger Theory": Toll-like Receptor 9 Stimulation Triggers Activation of Conventional CD8α+ and Plasmacytoid Dendritic Cells En Route to Enhancing FVIII Inhibitor Formation." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-143259.
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Inhibitor formation is the most serious complication of FVIII replacement therapy for hemophilia A. The long-standing "danger theory" posits that inhibitors may form as part of collateral damage from immune response to a primary challenge such as an infection or vaccination. Innate immune signaling, for example through Toll-like receptors (TLRs), could be one way of triggering or reinforcing unwanted immune responses. However, the danger hypothesis has been contradicted by recent reports showing no increase in inhibitor formation in boys and animal models with hemophilia when FVIII was administered concurrently with vaccines. The aim of this study was to elucidate the influence of TLR9 signaling on FVIII inhibitor formation in hemophilia A mice. Hemophilia A (F8e16-/-) B6/129 mice were co-injected IV with FVIII (1.5 IU) and ODN-1826 (a class B CpG oligodeoxynucleotide, 50 µg), which is a TLR9 agonist. Control mice were naïve or received FVIII only. Blood samples and spleens were collected for Bethesda assay and flow cytometry analysis 3h, 24h, 2, 3 and 7 days or 2, 4, 6 and 8 weeks after a single or repeated once-weekly injections. After four weeks, mice co-injected with FVIII and ODN-1826 (n=4) showed ~15-fold higher inhibitor titers (median 2667 BU/mL) than mice injected with FVIII only (median 181.4 BU/mL; n=15). We also found significantly higher T follicular helper (Tfh; CD4+CXCR5+PD1+Bcl6―) [F (7, 96) = 9.801, p<0.0001] and Germinal Center (GC) B cell numbers (CD19+GL7+CD95+) [F (6, 92) = 11,53, p<0.0001] in the spleen after 4, 6 and 8 weeks of co-injections, with the Tfh numbers being 1.3-, 12.2- and 1.65-fold, while GC B cell numbers being 2.9-, 5.3- and 1.1-fold higher, respectively, compared to mice injected with FVIII only. GC B cell numbers correlated with inhibitor titers [r(31)=0.52, p=0.002]. We also investigated dendritic cell (DC) responses after a single injection of FVIII or co-injection with ODN-1826. We found increased numbers of monocyte-derived DCs (moDCs; CD11chighMHCII+CD11b+ CD64+MAR-1+) in the co-injected group at all time points (3, 24, 48, 72 hours and 1 week after a single injection; n=4-5 per group) with the peak number (~10-fold higher compared to naïve mice; p=0.0002) being reached 72 hours and remaining similarly elevated at 1 week. However, levels of activation markers CD86 and MHCII on moDCs in both injected groups were not significantly elevated. The moDC numbers were also ~2.5-fold higher in the FVIII only group than in naïve animals at one week post-administration, but the difference was not statistically significant. Conversely, exposure to FVIII with or without ODN-1826 did not significantly affect the number of CD8α+CD11b- DCs, but this subset showed >2-fold upregulation of both CD86 and MHCII in the co-injected group 3h and 24h after injection (n=5-11, p<0.01). We further found increased numbers of plasmacytoid DCs (pDCs; CD11c+CD11b―PDCA+) but the difference was significant only in the co-injected group at d1 and d7 after injection (~2-fold higher than the naïve group; n=4-16 per group, p<0.05). This DC subset also showed upregulated CD86 and MHCII levels ~2-fold in the co-injected group, with difference between CD86 levels showing significance (p=0.0024). We next examined an interferon signature in pDCs by intracellular cytokine staining and found that the cells from co-injected mice had ~2-fold higher levels of IFNβ (p=0.0001, n=5 per group). We propose that TLR9 stimulation enhances FVIII inhibitor formation in hemophilia A mice through recruitment and/or activation of conventional CD8α+ and plasmacytoid dendritic cells. The narrowing differences in Tfh and GC B cell numbers between the FVIII only and ODN-1826 co-injected groups at week 8 suggest that TLR9 stimulation accelerates GC formation in response to FVIII, which otherwise may reach a similar magnitude, but it takes longer. Also, our results suggest that it may be premature to put the danger theory to rest. The outcome of an immune challenge may vary depending on which innate immune receptor is concurrently stimulated. Notably, all vaccinations tested in the animal study showing no link to inhibitor formation were against pathogens with genomes composed of single-stranded RNA (measles, mumps, rubella and influenza viruses), which does not activate TLR9. Therefore, the impact of vaccination against single-stranded DNA pathogens that can stimulate TLR9, such as VZV, may be worth further investigation. Disclosures Herzog: Takeda Pharmaceuticals: Patents & Royalties.
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Jelley-Gibbs, Dawn, Carolyn Winfrey, Sheri Eaton, and Laura Haynes. "Protective efficacy of CD4 memory T cells depends on route of administration of inactivated influenza vaccine (113.31)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 113.31. http://dx.doi.org/10.4049/jimmunol.188.supp.113.31.
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Abstract Studies aimed at determining the impact route of influenza vaccination has on vaccine efficacy revealed reduced protection against influenza virus challenge afforded by intranasal delivery compared to subcutaneous delivery of inactivated H1N1 influenza A virus. Both vaccine routes induced similar anti-viral antibody titers, similar numbers of anti-viral CD4 T cells, and undetectable anti-viral CD8 T cell responses. Further analysis of vaccine-induced CD4 memory T cell responses revealed that CD4 memory T cells primed in the lung draining lymph nodes were defective in recruiting anti-viral CD8 effectors to the lungs during challenge infections compared to the recruitment of CD8 effectors to the lungs by peripherally primed CD4 memory T cells. Since the influx of anti-viral CD8 effector T cells to the airways during influenza virus infection is a key event for virus control and elimination, we assayed for the expression of type-1 chemoattractants in the respiratory tract of vaccinated mice following challenge infection and discovered reduced lung expression of chemoattractants in the presence of intranasally primed CD4 memory T cells. We also determined that the presence of intranasally primed CD4 memory T cells reduced the ability of pulmonary antigen presenting cells to stimulate CD8 effectors directly ex vivo. We are currently assessing whether route of influenza vaccination also impacts susceptibility to secondary bacterial pneumonia following influenza challenge.
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Hemann, Emily, Sang-Moo Kang, and Kevin Legge. "Pulmonary vaccination against influenza virus induces a protective CD8 T cell response, which is regulated by APCs within the lungs (P6154)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 66.10. http://dx.doi.org/10.4049/jimmunol.190.supp.66.10.
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Abstract Recently there has been a renewed interest in the development of novel pulmonary influenza A virus (IAV) vaccines. CD8 T cells play an important role in clearance of IAV, and our prior studies demonstrate a key role for dendritic cells (DCs) in activation of IAV-specific CD8 T cells in the lymph nodes and maintenance in the lungs during IAV infections. Herein, we determined the role of pulmonary vaccine-induced CD8 T cells in protection from IAV challenge and the requirements for generation and maintenance of such CD8 T cell immunity. Our data demonstrates vaccination with IAV virus-like particles (VLPs) containing IAV HA and M1 leads to a significant increase in HA533-specific CD8 T cells. These VLP-specific CD8 T cells mediate protection of mice challenged with lethal doses of either homo- or heterosubtypic IAVs containing the HA533 epitope. Our preliminary results suggest interactions between DCs and effector T cells within the lungs are required following vaccination for maximal pulmonary VLP-specific CD8 T cell responses. Currently, we are investigating the contribution of inflammation and the APC subsets required in generation, boosting, and maintenance of vaccine-specific CD8 T cells during pulmonary vaccination. Collectively, our results highlight an important role for CD8 T cell mediated protection after i.n. vaccination and the seminal role pulmonary APCs play in activating and maintaining local vaccine-specific CD8 T cell responses against IAV in the lungs.
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Uddback, Ida Elin Maria, Emily Cartwright, Amalie Skak Schøller, Sarah L. Hayward, Jenny Lobby, Shiki Takamura, Allan R. Thomsen, Jacob E. Kohlmeier, and Jan Pravsgaard Christsensen. "Persistent antigen can maintain lung resident memory CD8 T cells long-term." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 129.2. http://dx.doi.org/10.4049/jimmunol.202.supp.129.2.
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Abstract A sub-population of memory T cells, tissue resident memory T cells (TRM), have in recent years gained attention for their indispensable role in heterologous protection against respiratory viruses. For this reason, they are of great interest for vaccine research. However, the number of lung TRM decline within a few months after infection and researchers have been unable to determine how the TRM population, and protection, can be made to last long-term in the lung. We have previously shown that an Adenovirus expressing nucleoprotein (AdNP) from influenza A virus induce CD8 T cell mediated heterosubtypic immunity lasting up to at least 8 months post vaccination when administered locally and systemically, but the underlying reason was not investigated. Here, we show that the number of CD8 T cell in the lung induced by AdNP is significantly higher compared to cells induced by an influenza infection. Using AdNP, we show that CD8 TRM in the lung can be maintained for at least one year post-vaccination. Our results revealed that lung TRM continued to proliferate in-situ 8 months after AdNP vaccination. Importantly, this required pulmonary vaccination and antigen persistence in the lung, as non-respiratory vaccination routes failed to support lung TRM maintenance. Additionally, parabiosis experiments show that in AdNP vaccinated mice the lung TRM pool is sustained by continual replenishment from circulating memory CD8 T cells that differentiate into lung TRM, a phenomenon not observed in influenza infected parabiont partners. Concluding, these results demonstrates requirements for long-lived cellular immunity to influenza virus, knowledge that could be utilized in future vaccine design.
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Schotsaert, Michael, Angela Choi, Jan Spitaels, Andrea Joselin Morales Mina, and Adolfo Garcia-Sastre. "Infection-permissive immunity against influenza virus provided by vaccination prevents loss of alveolar macrophages and modulates virus-induced cross-reactive cellular immune responses during subsequent influenza infections." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 147.6. http://dx.doi.org/10.4049/jimmunol.198.supp.147.6.
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Abstract Conventional influenza vaccines aim at the induction of virus-neutralizing antibodies. Influenza viruses can escape neutralization by antibodies through antigenic drift or shift or because antibody levels diminish. We wondered to what extent infection-permissive immunity provided by a trivalent inactivated influenza virus vaccine (TIV) could modulate disease and virus-induced host immune responses after homologous H1N1 infection. We first focused on alveolar macrophages, cells that are transiently lost during influenza infection in the mouse-influenza challenge model. Later we focused on how vaccine-induced immunity modulates induction of cross-reactive CD8+ T cells by virus infection. TIV vaccination did not result in detectable HI titers but correlated with lower viral lung titers and faster recovery after challlenge. Alveolar macrophages were abolished at 7dpi in negative control mice, but not in TIV-vaccinated mice. TIV vaccination allowed the induction but also affected levels of cross-reactive NP-specific CD8+ T cell responses, which correlated with protection against heterosubtypic H3N2 virus. The effect of TIV vaccination on TCR Vbeta-region bias of CD8+ T cells after secondary challenge with H3N2 virus was also investigated. These results suggest that suboptimal vaccination with conventional influenza vaccines may still positively modulate disease outcome, thereby allowing induction of heterosubtypic immunity by virus infection.
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Crowe, Sherry R., Stephen J. Turner, Shannon C. Miller, Alan D. Roberts, Rachel A. Rappolo, Peter C. Doherty, Kenneth H. Ely, and David L. Woodland. "Differential Antigen Presentation Regulates the Changing Patterns of CD8+ T Cell Immunodominance in Primary and Secondary Influenza Virus Infections." Journal of Experimental Medicine 198, no. 3 (July 28, 2003): 399–410. http://dx.doi.org/10.1084/jem.20022151.
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The specificity of CD8+ T cell responses can vary dramatically between primary and secondary infections. For example, NP366–374/Db- and PA224–233/Db-specific CD8+ T cells respond in approximately equal numbers to a primary influenza virus infection in C57BL/6 mice, whereas NP366–374/Db-specific CD8+ T cells dominate the secondary response. To investigate the mechanisms underlying this changing pattern of immunodominance, we analyzed the role of antigen presentation in regulating the specificity of the T cell response. The data show that both dendritic and nondendritic cells are able to present the NP366–374/Db epitope, whereas only dendritic cells effectively present the PA224–233/Db epitope after influenza virus infection, both in vitro and in vivo. This difference in epitope expression favored the activation and expansion of NP366–374/Db-specific CD8+ memory T cells during secondary infection. The data also show that the immune response to influenza virus infection may involve T cells specific for epitopes, such as PA224–233/Db, that are poorly expressed at the site of infection. In this regard, vaccination with the PA224–233 peptide actually had a detrimental effect on the clearance of a subsequent influenza virus infection. Thus, differential antigen presentation impacts both the specificity of the T cell response and the efficacy of peptide-based vaccination strategies.
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Luu, Tracy NK, Brock Kingstad-Bakke, Chandramaik Marinaik, Autumn Rose Larsen, and Marulasiddappa R. Suresh. "Role of NFKB signaling in Respiratory Epithelial Cells in Vaccine-Induced T Cell Immunity to Influenza." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 234.21. http://dx.doi.org/10.4049/jimmunol.204.supp.234.21.
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Abstract Respiratory epithelial cells (RECs) express Toll-like receptors (TLRs), produce both pro-inflammatory and anti-inflammatory molecules and function as immunological rheostats in the respiratory tract. The role of RECs in T cell responses to mucosal vaccination remains unknown. We have identified a combination adjuvant consisting of acrylic acid polymers in a nanoemulsion (Adjuplex; ADJ) and TLR4 agonist (glucopyranosyl lipid adjuvant; GLA) that elicits potent CD8 and CD4 T cell responses in the respiratory tract. Using mice (NFKB-REC) that conditionally lack NF-KB signaling in the RECs, we addressed the role of NFKB-dependent REC responses in regulating primary T cell responses to influenza virus nucleoprotein (NP), following intranasal vaccination with ADJ, GLA or ADJ+GLA. Surprisingly, we found that loss of REC NFKB signaling did not affect the magnitude of primary or recall antigen-specific T cell responses in the lungs and airways. Further, mucosal imprinting of CD8 T cells, as evidenced by expression of CD103 and CD49a, was minimally affected in NFKB-REC mice. Greater percentages of effector CD8 T cells in NFKB-REC mice expressed KLRG-1, regardless of the adjuvant but effector CD8 T cells in GLA mice showed elevated levels of CX3CR1, CD49a and granzyme B following challenge with influenza A virus. Preliminary evidence suggests that vaccine-induced T cell-dependent protection against influenza virus might be impaired in NFKB-REC mice.
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Haining, W. Nicholas, J. Evans, N. Seth, G. Callaway, K. Wucherpfennig, L. Nadler, and E. Guinan. "Rapid T Cell Response to Vaccination Can Occur without Antibody Response in Children Post HSCT." Blood 104, no. 11 (November 16, 2004): 2235. http://dx.doi.org/10.1182/blood.v104.11.2235.2235.
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Abstract Vaccination is widely used to improve pathogen-specific immunity in patients post HSCT, but it is not known whether patients can mount an effective T cell response to vaccine antigens (vAg). Moreover the relationship between T and B cell response to vAg has not been studied. We hypothesized that a sufficiently sensitive assay of T cell response to vAg would allow vaccination to be used as a tool to measure immune recovery post HSCT and improve vaccine design. We therefore: (1) developed a flow-cytometry-based approach to quantify and characterize T cells specific for vAg; (2) validated it by measuring T cell immunity to influenza A in normal donors; and (3) characterized the T and B cell response to influenza vaccination in pediatric HSCT patients. PBMC were labeled with CFSE and stimulated in vitro with whole influenza Ag. Ag-specific T cells were sensitively detected by their proliferation (loss of CFSE fluorescence) and simultaneous expression of the activation marker HLA-DR. Proliferating/active T cells could be readily detected after stimulation with influenza A Ag in healthy adult (n=4) and pediatric (n=19) donors but were absent in control conditions. Both CD4+ and CD8+ T cell proliferation was detected in all donors but one, and in children as young as 6mo. Staining with MHC I- and MHC II-tetramers confirmed that the proliferating/active population contained T cells specific for immunodominant CD8+ and CD4+ epitopes, demonstrating that vAg were processed and presented to epitope-specific T cells. To characterize the phenotype of influenza-specific T cell memory, we separated memory and naive CD4+ cells prior to antigen-stimulation. Antigen-experienced (CD45RA−/CCR7−) but not naive (CD45RA+/CCR7+) T cells proliferated to vAg confirming that the assay detected pre-existing influenza-A-specific T cell memory. We next assessed Influenza-A-specific T cell immunity before and after influenza vaccination in five pediatric HSCT recipients (mean age 10.6y, range 5–15y; mean time from transplant 13m, range 3–21m). Prior to vaccination the CD4 proliferation to influenza-A was a mean of 3.3% (range 0.04–11%). Following vaccination CD4 proliferation increased significantly in all patients (mean 19.0%, range 6.9%–31.8%, p=0.02). This increase was specific as proliferation to control Ag was unchanged. Influenza-A CD8+ proliferation also increased in 3 of 5 patients but was not statistically significant for the group consistent with the limited efficacy of soluble vAg in inducing CD8+ T cell response. All patients had detectable influenza-A-specific IgG levels prior to vaccination but despite a T cell response to vaccination in all patients, none had a significant increase in IgG level following vaccination. Only one patient had an IgM response; this patient also had the highest influenza-A-specific CD4 proliferation before and after immunization suggesting that there may be a threshold of T cell response required for a B cell response. Using a novel assay we demonstrate that a T cell response to vaccination can occur without an accompanying B cell response. This assay provides a more sensitive measure of immunity to vaccination and allows vaccine response to be used as a benchmark of strategies to accelerate post-HSCT T cell reconstitution.
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Kang, Chang Kyung, Hang-Rae Kim, Kyoung-Ho Song, Bhumsuk Keam, Seong Jin Choi, Pyoeng Gyun Choe, Eu Suk Kim, et al. "Cell-Mediated Immunogenicity of Influenza Vaccination in Patients With Cancer Receiving Immune Checkpoint Inhibitors." Journal of Infectious Diseases 222, no. 11 (June 1, 2020): 1902–9. http://dx.doi.org/10.1093/infdis/jiaa291.
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Abstract Background We assessed cell-mediated immune (CMI) responses of influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs), which remain elusive. Methods Vaccine-elicited CMI responses in patients receiving ICIs or cytotoxic agents were investigated by flow cytometry. Polyfunctional cells were defined as T cells that express 2 or more of interleukin 2 (IL-2), interleukin 4 (IL-4), interferon gamma (IFN-γ), and CD107a. An adequate CMI response was defined as an increase of polyfunctional T cells against both H1N1 and H3N2 strains. Results When comparing ICI (n = 11) and cytotoxic chemotherapy (n = 29) groups, H1N1-specific IL-4 or IFN-γ–expressing CD4+ T cells, IL-2, IL-4, IFN-γ, or CD107a-expressing CD8+ T cells, H3N2-specific IFN-γ–expressing CD4+ T cells, and CD107a-expressing CD8+ T cells were more frequent in the ICI group. Fold changes in polyfunctional H3N2-specific CD4+ (median, 156.0 vs 95.7; P = .005) and CD8+ (155.0 vs 103.4; P = .044) T cells were greater in the ICI group. ICI administration was strongly associated with an adequate CMI response for both CD4+ and CD8+ T cells (P = .003). Conclusions CMI responses following influenza vaccination were stronger in the ICI group than in the cytotoxic chemotherapy group. Influenza vaccination should be strongly recommended in patients with cancer receiving ICIs.
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Wagar, Lisa, Janet McElhaney, and Tania Watts. "Human influenza-specific effector and memory CD8 T cells from older adults show signs of terminal differentiation and senescence (104.3)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 104.3. http://dx.doi.org/10.4049/jimmunol.186.supp.104.3.
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Abstract Little is known about normal human aging and its effects on the function of T cells specific for acutely infecting pathogens. To address this issue, we conducted a multicolour flow cytometry study of older persons’ responses to influenza virus challenge ex vivo. Young and elderly donors were recruited in the fall of 2008. PBMCs were stained directly ex vivo or stimulated with A/Puerto Rico/8/34 (PR8) for 18 hours and assessed for functional markers. The data show that most donors have pre-existing influenza-specific T cells (measured by IFNγ) that are reactivated by PR8, although older donors had smaller pre-vaccination populations of flu-responsive T cells. Effector cells identified upon restimulation with influenza displayed a more terminally differentiated phenotype in older compared to younger adults. This phenotype did not change post-vaccination with trivalent inactivated vaccine, which lacks significant internal viral proteins and is a poor inducer of CD8 T cell responses. For HLA-A2+ donors, it was determined by tetramer staining that elderly influenza-specific CD8 T cells express higher levels of senescence markers KLRG1 and CD57 compared to young controls. Our study shows that influenza specific effector and memory T cells from older individuals show signs of terminal differentiation and senescence. Thus, as has been shown for persistent life-long infections, memory CD8 T cells to an acutely infecting pathogen show signs of deterioration with age.
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Zheng, Ming Z. M., Svenja Fritzlar, Zhongfang Wang, Tiong Kit Tan, Katherine Kedzierska, Alain Townsend, Patrick C. Reading, and Linda M. Wakim. "Cutting Edge: High-Dose Live Attenuated Influenza Vaccines Elicit Pulmonary Tissue-Resident Memory CD8+ T Cells in the Face of Pre-Existing Humoral Immunity." Journal of Immunology 209, no. 10 (November 15, 2022): 1832–36. http://dx.doi.org/10.4049/jimmunol.2200577.
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Abstract In this study, we investigated how pre-existing Ab immunity to influenza virus established from prior immunizations affects the development of CD8+ T cell responses evoked after vaccination with a live attenuated vaccine. Using a mouse model and a panel of live attenuated influenza virus vaccine candidates (cold adapted and single cycle), we show that pre-existing influenza-specific Abs directed against the vaccine backbone attenuate the size and quality of the vaccine-induced CD8+ T cell response. Importantly, we show that increasing the vaccine dose can overcome this impediment, resulting in improved vaccine-induced circulating and tissue-resident memory CD8+ T cell responses, which were protective against heterologous influenza challenge. Thus, the reduced size and quality of the T cell response elicited by a live attenuated influenza virus vaccine imparted by the influenza-specific Ab landscape of the vaccinee can be overcome by increasing vaccine dose.
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Lobby, Jenna L., Ida Elin Maria Uddback, Christopher D. Scharer, Tian Mi, Jeremy M. Boss, Allan R. Thomsen, Jan Pravsgaard Christensen, and Jacob E. Kohlmeier. "Identifying mechanisms that enhance the longevity of tissue-resident memory CD8+ T cells in the lung." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 103.24. http://dx.doi.org/10.4049/jimmunol.206.supp.103.24.
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Abstract Lung tissue-resident memory CD8+ T cells (TRM) are crucial mediators of cellular immunity against influenza viruses, but the number of these cells in the lung tissue gradually declines in the months following influenza infection. Recently, we showed that intranasal immunization with a replication-deficient adenovirus that expresses the nucleoprotein from influenza A virus (AdNP) results in long-term maintenance of lung CD8+ TRM for up to 1-year post-immunization. However, the mechanism(s) that promote this enhanced longevity of FluNP-specific CD8+ lung TRM remain unknown. Using a combination of mouse infection models, flow cytometry, and RNA-sequencing, we compared CD8+ T cells from the airways, lungs, and spleen of AdNP-immunized or influenza x31-infected mice. We found that CD8+ TRM in the lungs of AdNP-immunized mice show increased homeostatic turnover and hallmarks of persistent antigen stimulation in the lung. However, RNA-sequencing analysis comparing lung CD8+ TRM from AdNP-immunized and x31-infected mice at 1-month and 1-year post-immunization showed only minor variations that did not fully explain the differences in lung TRM persistence. Lineage tracing experiments using a Cre recombinase-expressing Adenovirus (AdCre) identified alveolar macrophages as the primary cell type harboring persistent antigen in the lung. Together, these results define one mechanism for enhancing the durability of lung TRM, which is an important consideration for the design of future cell-mediated influenza vaccines
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Lobby, Jenna L., Ida Uddback, Emily Cartwright, Sarah L. Hayward, Shiki Takamura, Allan R. Thomsen, Jan Christensen, and Jacob E. Kohlmeier. "Identifying mechanisms that enhance the longevity of tissue-resident memory T cells in the lung." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 85.5. http://dx.doi.org/10.4049/jimmunol.204.supp.85.5.
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Abstract Lung tissue-resident memory T cells (TRM) are crucial mediators of cellular immunity against influenza viruses, but the number of these cells in the lung tissue gradually declines in the months following influenza infection. Recently, we showed that intranasal immunization with a replication-deficient Adenovirus that expresses the nucleoprotein from influenza A virus (AdNP) results in long-term maintenance of lung CD8+ TRM for up to 1-year post-immunization. However, the mechanism(s) that promote this enhanced longevity of CD8+ lung TRM remain unknown. Using a combination of mouse infection models, flow cytometry, and RNA-sequencing, we compared CD8+ T cells from the airways, lung, and spleen from AdNP-immunized or influenza x31-infected mice. We found that CD8+ TRM in the lungs of AdNP-immunized mice show increased homeostatic turnover and encounter persistent antigen in the lung. In addition, parabiosis experiments suggest that the influenza-specific CD8+ lung TRM pool is maintained in AdNP-immunized mice by continual recruitment of circulating TEM into the lung TRM pool. RNA-sequencing analysis comparing CD8+ lung TRM from AdNP-immunized and x31-infected mice at 1-month and 1-year post-immunization showed only minor variations that did not fully explain the differences in lung TRM persistence. We are currently investigating how antigen is maintained in the lung following AdNP immunization using microscopy and Cre recombinase-expressing Adenovirus (AdCre) to identify antigen presenting cells harboring antigen long-term in the lung. The results of this study will identify mechanisms that improve the durability of cellular immunity, and will thus inform future design of cell-mediated influenza vaccines.
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Carey, Alison, Donald Gracias, Jillian Thayer, Jennifer Hope, Yvonne Mueller, and Peter Katsikis. "Impaired CD8+ T cell responses to influenza infection in neonatal mice are due to the immature T cell receptor repertoire (VIR2P.1020)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 75.9. http://dx.doi.org/10.4049/jimmunol.192.supp.75.9.
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Abstract To understand the role of virus antigen-specific CD8+ T cell responses in neonates during respiratory viral infection, we developed a model where 3-day old C57Bl/6 mice were infected intranasally with influenza type A virus strain A PR/8/34 (H1N1). When these neonatal mice are infected with influenza virus they mount a greatly reduced and delayed lung NP(366-374)-specific primary CD8+ T cell response. To investigate what was responsible for the reduced response, we performed adoptive transfers of TCR-transgenic OVA(257-264)-specific (OT-I) CD8+ T cells into hosts infected with recombinant influenza virus WSN-OVA, which expresses the OVA(257-264) peptide. These studies revealed that naïve adult OT-I cells expand equally well in neonatal and adult hosts, which excludes the neonatal environment as an inhibitor of the CD8+ T cell response. When naïve neonatal OT-I cells were transferred into neonatal and adult hosts, these neonatal OT-I cells expanded equally as well as adult OT-I cells, excluding an intrinsic defect in the neonatal CD8+ T cells. These studies demonstrate that the TCR repertoire of neonates is responsible for reduced CD8+ T cell immunity in neonates, not a suppressive environment or intrinsic signaling defects. Finally, despite impaired primary response, animals primed as neonates exhibited normal secondary responses to influenza virus. These findings raise important issues that need to be taken into consideration for vaccination of neonates.
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AINSUA-ENRICH, EROLA, Ibrahim Hatipoglu, Sapana Kadel, Sean Turner, Jinny Paul, and Susan Kovats. "IRF4-dependent DCs promote the establishment of CD8+ T cell memory during influenza infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 203.5. http://dx.doi.org/10.4049/jimmunol.198.supp.203.5.
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Abstract The transcription factor IRF4 governs the development and function of CD11b+ dendritic cells (DCs). To determine the role of IRF4-dependent DCs in influenza infection, we compared responses of wild-type and CD11c-cre-Irf4f/f(KO) mice. The KO mice lack one lung-resident CD11b+ DC subset, and the other DC subsets lack IRF4. Upon infection with A/PuertoRico/8/34 virus, KO lung DCs contained increased IL-12 and reduced IL-10 RNA, which correlated with elevated numbers of CD103+ lung migratory DCs in the mLN. Consistent with this, KO mice showed greater numbers of T-bet+ and IFNg+ influenza antigen-specific CD8+ and CD4+ T cells, reduced numbers of Foxp3+ T regulatory cells, and decreased numbers of CD8+ T memory precursor cells. These altered effector T cell populations in KO mice impacted the memory T cell response to influenza virus. Numbers of virus-specific lung resident memory CD8+ T cells were significantly reduced in KO mice. Upon challenge with heterosubtypic virus, KO mice showed deficient expansion of virus-specific IFNγ+ CD8+ T cells. Taken together, these data show that KO mice mount a stronger antiviral T cell response upon primary infection but then have a weaker CD8+ T cell memory response to heterosubtypic virus. This supports the hypothesis that during influenza infection, the functional responses of IRF4-dependent DCs lead to increased differentiation of CD8+ memory precursor T cells and numbers of lung resident CD8+memory T cells.
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Chirkova, T. V., A. N. Naykhin, G. D. Petukhova, D. A. Korenkov, S. A. Donina, A. N. Mironov, and L. G. Rudenko. "Memory T-Cell Immune Response in Healthy Young Adults Vaccinated with Live Attenuated Influenza A (H5N2) Vaccine." Clinical and Vaccine Immunology 18, no. 10 (August 3, 2011): 1710–18. http://dx.doi.org/10.1128/cvi.05116-11.
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ABSTRACTCellular immune responses of both CD4 and CD8 memory/effector T cells were evaluated in healthy young adults who received two doses of live attenuated influenza A (H5N2) vaccine. The vaccine was developed by reassortment of nonpathogenic avian A/Duck/Potsdam/1402-6/68 (H5N2) and cold-adapted A/Leningrad/134/17/57 (H2N2) viruses. T-cell responses were measured by standard methods of intracellular cytokine staining of gamma interferon (IFN-γ)-producing cells and a novel T-cell recognition of antigen-presenting cells by protein capture (TRAP) assay based on the trogocytosis phenomenon, namely, plasma membrane exchange between interacting immune cells. TRAP enables the detection of activated trogocytosis-positive T cells after virus stimulation. We showed that two doses of live attenuated influenza A (H5N2) vaccine promoted both CD4 and CD8 T-memory-cell responses in peripheral blood of healthy young subjects in the clinical study. Significant differences in geometric mean titers (GMTs) of influenza A (H5N2)-specific IFN-γ+cells were observed at day 42 following the second vaccination, while peak levels of trogocytosis+T cells were detected earlier, on the 21st day after the second vaccination. The inverse correlation of baseline levels compared to postvaccine fold changes in GMTs of influenza-specific CD4 and CD8 T cells demonstrated that baseline levels of these specific cells could be considered a predictive factor of vaccine immunogenicity.
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Liu, Yinping, Wu Yuet, Wenwei Tu, and Yu-Lung Lau. "Dendritic cell function and T cell responses to influenza viruses in patients with X-linked agammaglobulinemia (106.12)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 106.12. http://dx.doi.org/10.4049/jimmunol.186.supp.106.12.
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Abstract Immunodeficiency patients have high risks for influenza infection. X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by the deficiency of humoral immunity. Hence, cellular immune response becomes more important for these patients. However, little is known about the non-humoral immune responses to influenza virus in XLA patients. Here, we examined the APC function and T-cell immune responses to influenza viruses in XLA patients. Monocyte-derived immature dendritic cells (imMDDCs) from XLA patients had normal maturation upon inactivated influenza virus stimulation in terms of surface molecule expressions and cytokine productions. The T-cell stimulatory capacity of influenza virus-treated imMDDCs determined by mixed lymphocyte reactions from XLA patients was also similar as that from normal controls. There were no obvious side effects in XLA patients after administration of trivalent inactivated influenza vaccine (TIV). TIV significantly induced influenza virus-specific CD4 and CD8 T-cell responses in XLA patients. The frequencies of influenza virus-specific memory/effector CD4 and CD8 T cells in XLA patients are comparable to that in normal controls during 6 months of observation after vaccination. Our results indicated that XLA patients have normal APC function and T cell responses to influenza virus. Influenza vaccination may provide some benefits to XLA patients for influenza infection, at least reducing the severity of illness.
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Goronzy, Jörg J., James W. Fulbright, Cynthia S. Crowson, Gregory A. Poland, William M. O'Fallon, and Cornelia M. Weyand. "Value of Immunological Markers in Predicting Responsiveness to Influenza Vaccination in Elderly Individuals." Journal of Virology 75, no. 24 (December 15, 2001): 12182–87. http://dx.doi.org/10.1128/jvi.75.24.12182-12187.2001.
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ABSTRACT Elderly individuals are at high risk for morbidity and mortality when infected with influenza virus. Vaccinations with inactivated virus are less effective in the elderly due to the declining competency of the aging immune system. We have explored whether immunological parameters predict poor anti-influenza virus vaccine responses and can be used as biological markers of immunosenescence. One hundred fifty-three residents of community-based retirement facilities aged 65 to 98 years received a trivalent influenza vaccine. Vaccine-induced antibody responses were determined by comparing hemagglutination inhibition titers before and 28 days after immunization. The composition of the T-cell compartment was analyzed by flow cytometry and the sizes of three T-cell subsets, CD4+CD45RO+ cells, CD4+ CD28null cells, and CD8+ CD28null cells, were determined. Only 17% of the vaccine recipients were able to generate an increase in titers of antibody to all three vaccine components, and 46% of the immunized individuals failed to respond to any of the three hemagglutinins. The likelihood of successful vaccination declined with age and was independently correlated with the expansion of a particular T-cell subset, CD8+ CD28null T cells. The sizes of the CD4+ CD45RO+ memory T-cell and CD4+ CD28null T-cell subsets had no effect on the ability to mount anti-influenza virus antibody responses. Frequencies of CD8+ CD28null T cells are useful biological markers of compromised immunocompetence, identifying individuals at risk for insufficient antibody responses.
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Fuller, Michael John, John E. Bradley, and Troy D. Randall. "Redistribution of T follicular helper cells to the lungs of neonatal mice infected with influenza." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 147.5. http://dx.doi.org/10.4049/jimmunol.196.supp.147.5.
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Abstract The infant immune system responds poorly to both infection and vaccination, however the mechanisms responsible for impaired immune responses in neonates are incompletely understood. Here we analyzed T and B cell responses to influenza infection in neonatal mice. We found that neonatal mice were much more susceptible to primary influenza infection and cleared virus with delayed kinetics. Although CD8 T cell responses were slightly delayed in neonates compared to adults, neonates ultimately generated robust CD8 T cell responses. Following resolution of infection, however, the accumulation of tissue-resident memory (Trm) CD8 T cell responses was impaired in mice infected as neonates. In contrast, the appearance of influenza-specific CD4 T cells, including T follicular helper (Tfh) cells, was not delayed. Surprisingly, Tfh cells appeared in the lungs of neonatal mice, but not the lungs of adult mice. Tfh cells in the lungs of neonates correlated with the appearance of germinal center (GC) B cells and the formation of inducible bronchus-associated lymphoid tissue (iBALT) in the lungs. However, despite the appearance of local Tfh and GC B cells, the production of influenza-specific antibody was severely impaired in neonatal mice. Thus, despite the differentiation of influenza-specific Tfh in both lymphoid organs and lungs of neonatal mice, B cell-mediated immunity was still profoundly impaired. Nevertheless, while mice given a primary influenza infection as neonates had diminished Trm CD8 T cell responses and impaired B cell-mediated immunity, they were able to survive lethal rechallenge as adults, indicating that protective immunity could be generated in neonates.
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Adami, Alexander, Steven Szczepanek, Deirdre Lewis, Nayre Farrington, Sonali Bracken, Prabitha Natarajan, Eric Secor, Jr., Evan Jellison, Roger Thrall, and Biree Andemariam. "Disrupted T cell central memory following vaccination in patients with sickle cell disease (P4536)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 178.24. http://dx.doi.org/10.4049/jimmunol.190.supp.178.24.
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Abstract Increasing evidence suggests that a systemic state of disrupted immunity and inflammation accompanies sickle cell disease (SCD) despite the erythrocytic nature of the SCD mutation. Frequent infection plagues patients, who require aggressive vaccination from an early age. However, recent experimental and clinical evidence suggest diminished vaccine efficacy in SCD. We hypothesize that patients with SCD exhibit disrupted T cell memory in response to vaccination. We collected blood from nine healthy adult controls and eleven SCD patients before and 4-6 weeks after routine vaccination against influenza virus (IRB #11-026-1). Peripheral blood mononuclear cells were isolated and analyzed by flow cytometry. As previously reported, relative percentages of CD8+ central memory (CM) T cells significantly contracted following vaccination in control subjects (from 48.2 to 39.3, p < 0.01). Conversely, relative percentages of CD8+ CM T cells did not change in SCD patients (44.3 to 44.4, p > 0.05). Further, CD4+ CM T cells were significantly higher in patients with SCD versus controls before vaccination (58.7 vs. 44.7, p < 0.02) and trended higher following vaccination (56.8 vs. 40.7, p = 0.08). These data indicate that patients with SCD exhibit both disrupted CD8+ CM kinetics and altered CD4+ CM levels in the context of vaccination. Our findings suggest that at least a portion of the poor clinical response to vaccination in SCD may arise from disrupted T cell memory.
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Graham, Mary Beth, and Thomas J. Braciale. "Resistance to and Recovery from Lethal Influenza Virus Infection in B Lymphocyte–deficient Mice." Journal of Experimental Medicine 186, no. 12 (December 15, 1997): 2063–68. http://dx.doi.org/10.1084/jem.186.12.2063.
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In the adaptive immune response to most viruses, both the cellular and humoral arms of the immune system play complementary roles in eliminating virus and virus-infected cells and in promoting recovery. To evaluate the relative contribution of CD4+ and CD8+ effector T lymphocytes in virus clearance and recovery, we have examined the host response to lethal type A influenza virus infection in B lymphocyte–deficient mice with a targeted disruption in the immunoglobulin mu heavy chain. Our results indicate that naive B cell–deficient mice have a 50– 100-fold greater susceptibility to lethal type A influenza virus infection than do wild type mice. However, after priming with sublethal doses of influenza, immune B cell–deficient animals show an enhanced resistance to lethal virus infection. This finding indicates that an antibody-independent immune-mediated antiviral mechanism accounts for the increased resistance to lethal virus challenge. To assess the contribution of influenza-specific CD4+ and CD8+ effector T cells in this process, defined clonal populations of influenza-specific CD4+ and CD8+ effector T cells were adoptively transferred into lethally infected B cell–deficient mice. Cloned CD8+ effectors efficiently promoted recovery from lethal infection, whereas cloned CD4+ T cells conferred only partial protection. These results suggest that memory T lymphocytes can act independently of a humoral immune response in order to confer resistance to influenza infection in immune individuals. The potential implications of these results for vaccination against human influenza infection are discussed.
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McGee, Michael C., Sabrina Solouki, Candice B. Limper, Kaixiong Ye, Natalie F. Nidetz, Avery August, and Weishan Huang. "ITK regulates IL-10 production by CD8+ T cells and lung immunopathology during influenza infection." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 77.12. http://dx.doi.org/10.4049/jimmunol.204.supp.77.12.
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Abstract Influenza (flu) infections cause 250,000 deaths and 3–5 million cases of severe illness during the average flu season. Severe influenza infections are associated with a combination of strong pro-inflammatory and weak anti-inflammatory immune responses. Production of the anti-inflammatory cytokine IL-10 by T cells restricts immunopathology during flu infections, however our knowledge of the signaling pathways regulating IL-10 induction is limited. Using IL-10GFP reporter mouse models, we found that Interleukin-2 inducible T cell kinase (ITK), a critical component in T cell receptor (TCR) signaling, regulates the development of IL-10-producing CD8+ T cells during influenza A infection. Compared to wild type (WT) mice, Itk−/− mice displayed increased morbidity and mortality after influenza infection, accompanied by a significant reduction of IL-10 producing CD8+ T cells in the airways. Using the model antigen ovalbumin (OVA) and transgenic TCR specific for OVA in CD8+ T cells (OTI), along with an allele sensitive mutation in the ITK kinase domain, we determine that ITK regulates IL-10 production in antigen-specific CD8+ T cells in a kinase dependent manner. RNA sequencing and multiparametric flow cytometric analyses revealed that ITK differentially regulates the expression of cell surface markers and transcription factors that are involved in regulating T cell differentiation, effector and memory phenotypes. Together, our data suggests that ITK is a critical regulator of IL-10 production by CD8+ T cells and regulate immunopathology during influenza infection. Modulating ITK signaling may be a strategy for regulating immunopathology due to viral infections.
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Yu, Esther Dawen, Alba Grifoni, Aaron Sutherland, Hannah Voic, Eric Wang, April Frazier, Natalia Jimenez-Truque, et al. "Balanced Cellular and Humoral Immune Responses Targeting Multiple Antigens in Adults Receiving a Quadrivalent Inactivated Influenza Vaccine." Vaccines 9, no. 5 (April 23, 2021): 426. http://dx.doi.org/10.3390/vaccines9050426.
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The role of T cell immunity has been acknowledged in recent vaccine development and evaluation. We tested the humoral and cellular immune responses to Flucelvax®, a quadrivalent inactivated seasonal influenza vaccine containing two influenza A (H1N1 Singapore/GP1908/2015 IVR-180 and H3N2 North Carolina/04/2016) and two influenza B (Iowa/06/2017 and Singapore/INFTT-16-0610/2016) virus strains, using peripheral blood mononuclear cells stimulated by pools of peptides overlapping all the individual influenza viral protein components. Baseline reactivity was detected against all four strains both at the level of CD4 and CD8 responses and targeting different proteins. CD4 T cell reactivity was mostly directed to HA/NA proteins in influenza B strains, and NP/M1/M2/NS1/NEP proteins in the case of the Influenza A strains. CD8 responses to both influenza A and B viruses preferentially targeted the more conserved core viral proteins. Following vaccination, both CD4 and CD8 responses against the various influenza antigens were increased in day 15 to day 91 post vaccination period, and maintained a Th1 polarized profile. Importantly, no vaccine interference was detected, with the increased responses balanced across all four included viral strains for both CD4 and CD8 T cells, and targeting HA and multiple additional viral antigens.
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L’huillier, Arnaud G., Victor H. Ferreira, Cedric Hirzel, Yoichiro Natori, Jaclyn Slomovic, Terrance Ku, Katja Hoschler, et al. "Cell-Mediated Immune Responses After Influenza Vaccination of Solid Organ Transplant Recipients: Secondary Outcomes Analyses of a Randomized Controlled Trial." Journal of Infectious Diseases 221, no. 1 (September 24, 2019): 53–62. http://dx.doi.org/10.1093/infdis/jiz471.
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Abstract Background Despite annual immunization, solid organ transplant (SOT) patients remain at increased risk for severe influenza infection because of suboptimal vaccine immunogenicity. We aimed to compare the CD4+ and CD8+ T-cell responses of the high-dose (HD) and the standard-dose (SD) trivalent inactivated vaccine. Methods We collected peripheral blood mononuclear cells pre- and postimmunization from 60 patients enrolled in a randomized trial of HD versus SD vaccine (30 HD; 30 SD) during the 2016–2017 influenza season. Results The HD vaccine elicited significantly greater monofunctional and polyfunctional CD4+ and CD8+ T-cell responses against influenza A/H1N1, A/H3N2, and B. For example, median vaccine-elicited influenza-specific polyfunctional CD4+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza A/H1N1 (1193 vs 0 per 106 CD4+ T cells; P = .003), A/H3N2 (1154 vs 51; P = .008), and B (1102 vs 0; P = .001). Likewise, vaccine-elicited influenza-specific polyfunctional CD8+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza B (367 vs 0; P = .002). Conclusions Our study provides novel evidence that HD vaccine elicits greater cellular responses compared with the SD vaccine in SOT recipients, which provides support to preferentially consider use of HD vaccination in the SOT setting.
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Meilleur, Courtney Erin, Arash Memarnejadian, John K. McCormick, and S. M. Mansour Haeryfar. "Prior administration of staphylococcal enterotoxin B augments the CD8+ T cell response to influenza A virus." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 78.17. http://dx.doi.org/10.4049/jimmunol.196.supp.78.17.
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Abstract Staphylococcal enterotoxin B (SEB) is a bacterial protein capable of binding up to 20% of the entire T cell repertoire. T cells that have come into contact with SEB initially proliferate and secrete inflammatory cytokines; however, this is followed by anergy or death of the affected cells. This population of deleted or functionally inactivated cells is likely to include T cell clones that are important for immunity to other pathogens such as influenza A virus (IAV). For this reason, we hypothesize that SEB exposure will alter the magnitude and breadth of the CD8+ T cell response to IAV. Using mouse model of intraperitoneal vaccination with IAV, we found that prior exposure to SEB actually increased the number of IAV-specific CD8+ T cells for several IAV epitopes during the primary phase of the immune response. The number of cells specific for these epitopes remained elevated even after the peak of the primary CD8+ T cell response had passed. In addition, repetition of the first experiment with several different naturally circulating and lab-adapted strains of IAV gave similar results, showing that the effect of SEB on virus-specific CD8+ T cells is the same for a potentially diverse range of IAV strains. Furthermore, the ability of the CD8+ T cells to kill target cells pulsed with cognate IAV antigen was also enhanced after SEB exposure, for both primary and memory CD8+ T cells. Curiously, we did not observe an effect of SEB when it is given in the context of a replicative IAV infection in the lungs. This work reveals an unexpected role for SEB as an enhancer of CD8+ T cell immunity in this model.
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Ainsua-Enrich, Erola, Ibrahim Hatipoglu, Sapana Kadel, Sean Turner, Jinny Paul, Simar Singh, Harini Bagavant, and Susan Kovats. "IRF4-dependent DCs regulate T cell effector and memory responses in influenza virus infection." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 60.20. http://dx.doi.org/10.4049/jimmunol.200.supp.60.20.
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Abstract Dendritic cells (DCs) activate adaptive immune responses during respiratory virus infection. A number of transcription factors govern the development and function of tissue DCs, including IRF4. To determine the role of IRF4-dependent lung DCs in influenza virus infection, we studied CD11c-cre-Irf4f/f (KO) mice. In this KO, one lung resident CD11b+ DC subset is missing, and the other DC subsets lack IRF4. Upon infection with A/PuertoRico/8/34 virus, KO lung DCs contained increased IL-12 and reduced IL-10 RNA. This altered IL-12/IL-10 balance in KO mice led to increased numbers of T-bet+ IFNg+ influenza antigen-specific effector CD8+ and CD4+ T cells, yet reduced numbers of Foxp3+ T regulatory cells (Tregs) and CD8+ antigen-specific memory precursor effector cells (MPECs) at later stages of infection. The remaining MPECs in KO mice showed decreased expression of Foxo1 and Bcl6, key transcription factors important for T cell memory differentiation. This suggests that factors including IL-10 produced by IRF4-dependent DCs elicit a memory-biased transcriptional program in late CD8+ T cell effectors. Accordingly, KO lungs contained reduced numbers of resident CD8+ memory T cells (TRM) forty days post-infection. Upon rechallenge with heterosubtypic virus, KO mice showed deficient expansion of virus-specific IFNγ+ CD8+ T cells. Taken together, these data show that KO mice mount a stronger antiviral T cell response upon primary infection but then elaborate a weaker CD8+ T cell memory response to heterologous virus. Our data support the hypothesis that IRF4-dependent DCs normally act to promote the differentiation of CD8+ memory T cells during influenza virus infection.
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Frentsch, Marco, Regina Stark, Joanna Listopad, Sarah Meier, Axel Schulz, Sibel Durlanik, Thomas Blankenstein, and Andreas Thiel. "Identification and characterization of CD8+ T helper cells based on CD40L expression (155.1)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 155.1. http://dx.doi.org/10.4049/jimmunol.186.supp.155.1.
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Abstract CD8+ T cells are primarily regarded as cytotoxic cells. We have identified a substantial subset of CD40L expressing non-cytotoxic T-cells among primary human CD8+ T cells. CD40L+ CD8+ T cells exert diverse characteristic Th-cell functions such as activation of B cells, induction of DC maturation and secretion of cytokines such as IL-2, IFNγ, TNFα or IL-4. Up to 25% of total human central and effector memory CD8+ T cells express CD40L including cells specific for pathogens such as influenza, CMV and EBV, as well as yellow fever virus specific cells after primary vaccination. At next we assessed the functional relevance of CD40L expression on CD8+ T cells during a anti-tumor response. We challenged Rag1-/- mice with SV40 Tag expressing tumor cells and injected in parallel wt or CD40L-/- CD8+ T cells. Only application of CD40L competent wt CD8+ T cells prevented the establishment of tumors, whereas injection of CD40L-/- CD8+ T cells resulted in non-controlled tumor progression similar to non-treated tumors, although tumor-specific T cells were primed in these mice. Our results disclose an essential functional relevance of CD40L expressed by CD8+ T cells. Especially, in situations of reduced CD4+ T-cell help and MHC-II antigen presentation and/or limited danger signals CD40L+ CD8+ T cells may exert essential helper responsibilities for immunity and thus are potent candidate T cells to execute or support effective anti-tumor or anti-pathogen immune therapies.
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He, Ran. "Efficient control of chronic LCMV infection by CD4 T cell epitope-based heterologous prime-boost vaccination in a murine model." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 123.10. http://dx.doi.org/10.4049/jimmunol.198.supp.123.10.
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Abstract CD4+ T cells are essential for sustaining CD8+ T cell responses during chronic infection. The adoptive transfer of virus-specific CD4+ T cells has been shown to efficiently rescue exhausted CD8+ T cells. However, the question of whether endogenous virus-specific CD4+ T cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted CD8+ T cells remains unexplored. In this study, we developed a CD4+ T cell epitope-based heterologous prime-boost immunization strategy and examined the efficacy of this strategy using a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We primed chronically LCMV-infected mice with the Listeria monocytogenes vector expressing the LCMV glycoprotein-specific I-Ab-restricted CD4+ T cell epitope GP61-80 (LM-GP61) and subsequently boosted the primed mice with an influenza virus A (PR8 strain) vector expressing the same CD4+ T cell epitope (IAV-GP61). This heterologous prime-boost vaccination strategy elicited strong anti-viral CD4+ T cell responses, which further improved both the quantity and quality of the virus-specific CD8+ T cells and led to better control of viral loads. The combination of this strategy and the blockade of the programmed cell death-1 (PD-1) inhibitory pathway further enhanced anti-viral CD8+ T cell responses and viral clearance. Therefore, heterologous prime-boost immunization that selectively induces virus-specific CD4+ T cell responses in conjunction with inhibitory pathway blockade may represent a promising therapeutic approach to treating patients with chronic viral infection.
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Ulmer, Jeffrey B., Tong-Ming Fu, R. Randall Deck, Arthur Friedman, Liming Guan, Corrille DeWitt, Xu Liu, et al. "Protective CD4+ and CD8+ T Cells against Influenza Virus Induced by Vaccination with Nucleoprotein DNA." Journal of Virology 72, no. 7 (July 1, 1998): 5648–53. http://dx.doi.org/10.1128/jvi.72.7.5648-5653.1998.
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ABSTRACT DNA vaccination is an effective means of eliciting both humoral and cellular immunity, including cytotoxic T lymphocytes (CTL). Using an influenza virus model, we previously demonstrated that injection of DNA encoding influenza virus nucleoprotein (NP) induced major histocompatibility complex class I-restricted CTL and cross-strain protection from lethal virus challenge in mice (J. B. Ulmer et al., Science 259:1745–1749, 1993). In the present study, we have characterized in more detail the cellular immune responses induced by NP DNA, which included robust lymphoproliferation and Th1-type cytokine secretion (high levels of gamma interferon and interleukin-2 [IL-2], with little IL-4 or IL-10) in response to antigen-specific restimulation of splenocytes in vitro. These responses were mediated by CD4+ T cells, as shown by in vitro depletion of T-cell subsets. Taken together, these results indicate that immunization with NP DNA primes both cytolytic CD8+ T cells and cytokine-secreting CD4+ T cells. Further, we demonstrate by adoptive transfer and in vivo depletion of T-cell subsets that both of these types of T cells act as effectors in protective immunity against influenza virus challenge conferred by NP DNA.
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Uddback, Ida Elin Maria, Kristiana H. Laccette, Zheng-Rong Tiger Li, and Jacob E. Kohlmeier. "Lung-resident memory CD8+ T cells prevent transmission of respiratory viruses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 94.5. http://dx.doi.org/10.4049/jimmunol.204.supp.94.5.
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Abstract Lung tissue-resident memory CD8+ T cells (TRM) reduce viral replication and limit pathology following respiratory virus infections. In particular, TRM are crucial for protection against infections with heterosubtypic influenza viruses, where pre-existing antibody does not provide sterilizing immunity. In addition to providing individual host immunity, vaccination programs are designed to limit pathogen spread at population level. Despite the interest in lung TRM for intra-host protective immunity, their effect on the transmission respiratory viruses has been understudied due to the lack of animal models where influenza infection can be tracked longitudinally, and where the immunological parameters are easily identified and manipulated. To circumvent these issues, we used a luciferase-expressing Sendai virus, a natural mouse parainfluenza virus that readily transmits via the aerosol and contact routes, to evaluate the efficacy of lung TRM against transmission of respiratory viruses. Using a recombinant influenza virus expressing the immunodominant SenNP324–332Kb epitope to generate SenNP+ memory CD8+ T cells and IVIS imaging to non-invasively measure Sendai virus infection over time, we found that mice with pre-existing SenNP+ lung TRM don’t transmit Sendai virus to naïve mice when co-housed. In contrast, immunized mice that had pre-existing circulating effector memory CD8+ T cells (TEM), but no lung TRM, failed to prevent transmission of Sendai virus to naïve mice when co-housed. These results show the ability of lung TRM to contribute to herd immunity by preventing respiratory virus transmission and underscore the potential of a TRM-inducing vaccine for protection against respiratory viruses.
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Zhou, Angela, Lisa Wagar, Michael Wortzman, and Tania Watts. "Qualitative and quantitative effects of 4-1BBL in boosting pre-existing influenza immunity (VAC2P.923)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 72.1. http://dx.doi.org/10.4049/jimmunol.192.supp.72.1.
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Abstract Influenza virus induces an acute respiratory infection responsible for up to 500,000 annual deaths, primarily in older persons. CD8+ T cells against conserved influenza proteins confer heterotypic protection, potentially providing a “universal vaccine.” However, live infection only transiently boosts influenza-specific T cell memory, and immunity further declines with age. To improve the longevity of T cell memory, we investigated the effects of stimulating the TNFR-family member 4-1BB. To mimic vaccination of previously flu-immune adults, mice were infected with influenza A/HK-X31 and boosted intranasally one-month later with control replication-deficient adenovirus or adenovirus encoding influenza nucleoprotein (NP) alone (Ad-NP) or NP with 4-1BBL (Ad-NP-4-1BBL). 4-1BBL dramatically enhanced NP-specific CD8+ T cell responses at a dose where Ad-NP had minimal effects. 4-1BBL induced a remarkably long-lived effector-memory population that protects mice against lethal challenge into old age (>1 year old). Increasing the Ad-NP dose did not replicate these effects, and instead caused partial functional exhaustion. Preliminary analysis indicates that the 4-1BBL-induced effector memory T cells have increased expression of IL-7R as well as the transcriptional factor TCF-1 and an increased ratio of T-bet to Eomesodermin. Thus, 4-1BBL in a vaccine vector administered in flu-immune mice induces a potentially unique protective subset of memory CD8+ T cells.
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Barefoot, Brice E., Christopher Sample, and Elizabeth Ramsburg. "Post-exposure vaccination against influenza (132.4)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 132.4. http://dx.doi.org/10.4049/jimmunol.182.supp.132.4.
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Abstract Vaccines currently licensed for the prevention of influenza induce antibodies against the influenza hemagglutinin (HA) and neuraminidase (NA) contained in the vaccine preparation but require at least two weeks after immunization for the development of protective immunity. We have developed a novel vaccine based on recombinant vesicular stomatitis virus which expresses the influenza hemagglutinin (rVSV HA) and protects mice from lethal influenza challenge when the vaccine is administered intramuscularly shortly after delivery of the influenza challenge virus. To our knowledge ours is the first vaccine which effectively protects animals from lethal influenza challenge when delivered by a systemic route after influenza exposure has occurred. The mechanism(s) by which rVSV HA protects remain to be determined but induction of HA-specific immune responses is essential, because animals immunized with an empty rVSV vector were not protected equally. Our data are consistent with a model in which post-exposure rVSV HA vaccination induces an immediate antiviral cytokine response, followed by expansion of HA-specific cytotoxic CD8 T cells, which circulate to the respiratory tract and clear infected cells. Vaccinated animals do not have detectable serum neutralizing Ab to influenza during the acute phase of the infection, but antibody may be required at later timepoints for complete clearance of influenza.
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Reagin, Katie L., and Kimberly D. Klonowski. "Regulation of Respiratory CD8+ T cell Immunity by Suppressive Monocyte Derived Dendritic Cells (moDCs)." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 85.3. http://dx.doi.org/10.4049/jimmunol.204.supp.85.3.
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Abstract Active immune suppression can mediate the balance between protective cellular immunity and harmful immunopathology. This suppression can occur locally, at an infection site, or in regional draining lymph nodes (dLN). Immune regulation is of particular importance in sites such as the lung where aberrant immunopathology can result in loss of tissue function. We have recently identified a novel population of CD11b+CD103+CCR2+monocyte-derived dendritic cells (moDCs) which directly suppress CD8+ T cell proliferation in vitro. Respiratory infection with RNA viruses recruits these moDCs either exclusively to the dLN (after vesicular stomatitis virus infection) or both the dLN and site of viral replication (after influenza infection). Exclusive depletion of moDCs from the dLN using CCR2-DTR bone marrow chimeras results in enhanced respiratory CD8+ lung tissue resident memory cell formation. By contrast, depletion of moDCs from both the dLN and respiratory tract following influenza infection results in enhanced respiratory CD8+ T cell responses coupled with fatal immunopathology. Together, these data suggest that suppressive moDCs govern key aspects of respiratory immunity by regulating the function and development of long-lived CD8+ T cells, thereby balancing immunity and adverse pathology in the context of viral infection. Ongoing experiments seek to uncouple moDC interactions with CD8+ T cells in specific sites in order to better understand, and potentially beneficially modulate, CD8+ T cell immunity within the lung.
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Wilkins, Danice, Julia Tietze, Kory Alderson, Jon Weiss, Myriam Bouchlaka, Stephen Priest, Dennis Taub, et al. "Antigen nonspecific memory CD8 T cells expand and gain effector function in response to immunotherapy or to viral infection (131.28)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 131.28. http://dx.doi.org/10.4049/jimmunol.184.supp.131.28.
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Abstract Memory CD8 T cells (CD44hi+) have a wide distribution in peripheral blood, secondary lymphoid and non-lymphoid tissues and are hallmarked by their ability to respond rapidly to antigenic re-challenge. We observed that systemic cytokine immunotherapy (IT) results in the marked expansion of memory CD8 T cells due to the preferential expansion of pre-existing memory T cells and not the conversion of naïve (CD44lo+) T cells to an activated phenotype. These CD8 T cells express NKG2D and have cytolytic activity; however, a lack of increased CD25 and PD-1 expression suggests that the expansion and activation are independent of TCR engagement. Studies of CD8 T cells from OT-1 TCR transgenic mice after IT demonstrated the increased lysis of ova-negative tumor targets; moreover, the OT-1 CD8 T cells possessed a memory phenotype and lacked CD25 expression in the absence of ova vaccination. To determine if memory CD8 T cells play a role in pathogenic situations, mice were infected with influenza and tissues were examined for the presence of CD25-NKG2D+ memory CD8 T cells. Interestingly, these cells expanded rapidly in the lungs of infected mice but not peripheral tissues, indicating that memory T cells may play a role in the clearance of pathogen, regardless of antigen specificity. These data suggest that resident tissue memory CD8 T cells may act in reserve as innate effectors and thus bridge the gap between adaptive and innate immunity in cancer immunotherapy and viral infections.
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McGargill, Maureen, Rachael Keating, John Lukens, Tomer Hertz, Tarsha Harris, Benjamin Edwards, Blaine Creasy, Peter Doherty, and Paul Thomas. "Enhancing protection against highly pathogenic H5N1 avian influenza A viruses (170.31)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 170.31. http://dx.doi.org/10.4049/jimmunol.188.supp.170.31.
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Abstract Highly pathogenic H5N1 avian influenza A viruses pose a serious threat for a deadly pandemic. Vaccination is the most effective strategy for controlling influenza, however it is not possible to predict which H5N1 variants may acquire the ability to transmit efficiently between humans, and conserved epitopes between different subtypes do not induce sufficient immunity. Thus, a strategy to increase the efficacy of universal vaccines is essential for preventing a deadly pandemic. Others demonstrated that the immunosuppressive drug, rapamycin, paradoxically increased the number of memory T cells during LCMV infection. Thus, we examined whether rapamycin increases the number of memory T cells during influenza infection, and consequently enhances protection against a secondary infection with a heterosubtypic H5N1 strain. Mice were immunized with HKx31 (H3N2), treated with rapamycin for 30 days, and challenged with a modified H5N1 virus, ΔVn1203. We found rapamycin protected mice from a lethal ΔVn1203 infection, but not in the absence of a primary infection. Interestingly, rapamycin increased the number of influenza-specific CD8 T cells after the primary and secondary infection. However, memory CD8 T cells were not required for protection. Rather, CD4 T cells and B cells were critical for the enhanced survival following rapamycin treatment. These data suggest that rapamycin protects against a highly pathogenic, heterosubtypic influenza infection by altering the antibody response.
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Crabtree, Juliet Nicole, Wenqian He, Weihua Guan, Matthew S. Miller, and Erik J. Peterson. "Autoimmune variant PTPN22 is associated with impaired responses to influenza virus vaccination." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 193.5. http://dx.doi.org/10.4049/jimmunol.196.supp.193.5.
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Abstract High-affinity antibody production, T cell activation, and Interferon upregulation all contribute to protective immunity that occurs in humans following influenza immunization. Hematopoietic cell-specific PTPN22 encodes Lymphoid Phosphatase (Lyp), which regulates lymphocyte antigen receptor and Pattern Recognition Receptor (PRR) signaling. A PTPN22 variant R620W (LypW) predisposes to autoimmune and infectious disease, and confers altered signaling through antigen receptors and PRRs. We tested the hypothesis that LypW-bearing humans would have diminished immune response to trivalent influenza vaccine (TIV). LypW carriers exhibited decreased induction of influenza-specific CD4 T cells expressing effector cytokines, and failed to increase antibody affinity following TIV. No differences between LypW carriers and non-carriers were observed in virus-specific CD8 T cell responses, early interferon transcriptional responses, or myeloid APC costimulatory molecule upregulation. LypW association with defects in TIV-induced CD4 T cell expansion and antibody affinity maturation suggests that LypW may predispose to diminished capacity to generate protective immunity against influenza.
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Doornekamp, Laura, Rogier L. Goetgebuer, Katharina S. Schmitz, Marco Goeijenbier, C. Janneke van der Woude, Ron Fouchier, Eric C. M. van Gorp, and Annemarie C. de Vries. "High Immunogenicity to Influenza Vaccination in Crohn’s Disease Patients Treated with Ustekinumab." Vaccines 8, no. 3 (August 14, 2020): 455. http://dx.doi.org/10.3390/vaccines8030455.
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Influenza vaccination can be less effective in patients treated with immunosuppressive therapy. However, little is known about the effects of ustekinumab; an anti-IL-12/23 agent used to treat Crohn’s disease (CD), on vaccination response. In this prospective study, we assessed immune responses to seasonal influenza vaccination in CD patients treated with ustekinumab compared to CD patients treated with anti-TNFα therapy (adalimumab) and healthy controls. Humoral responses were assessed with hemagglutinin inhibition (HI) assays. Influenza-specific total CD3+, CD3+CD4+, and CD3+CD8+ T-cell responses were measured with flow cytometry. Fifteen patients treated with ustekinumab; 12 with adalimumab and 20 healthy controls were vaccinated for seasonal influenza in September 2018. Seroprotection rates against all vaccine strains in the ustekinumab group were high and comparable to healthy controls. Seroconversion rates were comparable, and for A/H3N2 highest in the ustekinumab group. HI titers were significantly higher in the ustekinumab group and healthy controls than in the adalimumab group for the B/Victoria strain. Post-vaccination T-cell responses in the ustekinumab group were similar to healthy controls. One-month post-vaccination proliferation of CD3+CD8+ T-cells was highest in the ustekinumab group. In conclusion, ustekinumab does not impair immune responses to inactivated influenza vaccination. Therefore, CD patients treated with ustekinumab can be effectively vaccinated for seasonal influenza.