Статті в журналах: "Immune cell activation"

1

Kerdiles, Yann, Sophie Ugolini, and Eric Vivier. "T cell regulation of natural killer cells." Journal of Experimental Medicine 210, no. 6 (June 3, 2013): 1065–68. http://dx.doi.org/10.1084/jem.20130960.

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In light of their role in the immune response against tumors and viruses, natural killer (NK) cells represent a promising target for immunotherapy. Before this target is reached, the various mechanisms that control NK cell activity must first be identified and understood. In the past decades, studies have identified two critical processes that prevent spontaneous NK cell–mediated autoimmune activation while maximizing the efficiency of these cells during an immune response. First is the education process, whereby NK cells adapt to their environment by sensing ligands for inhibitory and activating receptors. Second is the priming phase of NK cell activation, which arms NK cells with appropriate cytotoxic molecules during inflammation. New studies now indicate that NK cell proliferation, accumulation, and activation are also under the control of regulatory T cells that restrict availability of IL-2 released by activated CD4+ T cells. Together with other recent studies, these data highlight the importance of the adaptive immune system in the regulation of NK cell activity.

2

Ducloux, Didier, Jamal Bamoulid, Thomas Crepin, Jean-Michel Rebibou, Cecile Courivaud, and Philippe Saas. "Posttransplant Immune Activation." Cell Transplantation 26, no. 9 (September 2017): 1601–9. http://dx.doi.org/10.1177/0963689717735404.

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Cardiovascular disease is a major cause of morbidity, disability, and mortality in kidney transplant patients. Cumulative reports indicate that the excessive risk of cardiovascular events is not entirely explained by the increased prevalence of traditional cardiovascular risk factors. Atherosclerosis is a chronic inflammatory disease, and it has been postulated that posttransplant immune disturbances may explain the gap between the predicted and observed risks of cardiovascular events. Although concordant data suggest that innate immunity contributes to the posttransplant accelerated atherosclerosis, only few arguments plead for a role of adaptive immunity. We report and discuss here consistent data demonstrating that CD8+ T cell activation is a frequent posttransplant immune feature that may have pro-atherogenic effects. Expansion of exhausted/activated CD8+ T cells in kidney transplant recipients is stimulated by several factors including cytomegalovirus infections, lymphodepletive therapy (e.g., antithymocyte globulins), chronic allogeneic stimulation, and a past history of renal insufficiency. This is observed in the setting of decreased thymic activity, a process also found in elderly individuals and reflecting accelerated immune senescence.

3

Čemerski, Sašo, and Andrey Shaw. "Immune synapses in T-cell activation." Current Opinion in Immunology 18, no. 3 (June 2006): 298–304. http://dx.doi.org/10.1016/j.coi.2006.03.011.

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4

Xu, H., and M. Chen. "Immune cell activation in diabetic retinopathy." Acta Ophthalmologica 93 (September 23, 2015): n/a. http://dx.doi.org/10.1111/j.1755-3768.2015.0157.

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5

Xue, Ying, Fujia Lu, and Weimin Wang. "Ferroptotic cells augment T-cell activation and neuroinflammation." Ageing and Neurodegenerative Diseases 2, no. 3 (2022): 15. http://dx.doi.org/10.20517/and.2022.17.

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Since ferroptosis, a form of cell death characterized by aberrant lipid peroxidation, was proposed 10 years ago, its interaction with the immune system has been revealed gradually. On the one hand, immune cell-secreted cytokines are able to increase or suppress ferroptosis sensitivities of other cell types, such as tumor cells and fibroblasts. On the other hand, ferroptotic cell-released factors have the capacity to modulate the functions of neighboring immune cells, including dendritic cells, macrophages, and T cells. Identifying these immunomodulatory molecules generated during ferroptosis paves the way for developing novel immunotherapy strategies for treating cancer and autoimmune diseases.

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Kowalska-Kępczyńska, Anna, Mateusz Mleczko, Weronika Domerecka, Dorota Krasowska, and Helena Donica. "Assessment of Immune Cell Activation in Pemphigus." Cells 11, no. 12 (June 13, 2022): 1912. http://dx.doi.org/10.3390/cells11121912.

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(1) Background: Pemphigus is a blistering autoimmune disease of the skin and/or mucous membranes, characterised by the presence of specific autoantibodies directed against structural proteins of the human skin. Recent reports indicate that new haematological parameters, termed Extended Inflammation Parameters (EIP), can be used to assess the activation of immune cells during active inflammation. These include parameters assessing both neutrophil activation (NEUT-RI, NEUT-GI) and the number of activated lymphocytes (RE-LYMP). The aim of this study was to investigate the relationship between changes in NEUT-RI, NEUT-GI and RE-LYMP and the disease activity in patients with pemphigus. (2) Results: The study involved 32 patients with diagnosed different types of pemphigus. Neutrophil activation parameters (NEUT-RI and NEUT-GI) and lymphocytes (RE-LYMP) were significantly higher in these patients compared to the parameters in healthy participants (respectively p = 0.0127, p = 0.0011 and p = 0.0033). The increased quantity of activated lymphocytes (RE-LYMP) also correlated significantly with the extent of skin and/or mucosal lesions in patients assessed by the PDAI scale (p < 0.02). (3) Conclusions: The NEUT-RI, NEUT-GI and RE-LYMP parameters proved to be appropriate markers of inflammation severity in pemphigus, also in relation to local lesions, which was not possible with the inflammation markers (CRP, ESR) used so far on a routine basis.

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Roberts, Rebecca, Henry Leonard, Ilona Aylott, Douglas Best, Dan Rocca, Ben Thompson, Nunan Robert, and Louise Brackenbury. "Abstract 1844: Development of a high content screening (HCS) platform for novel cancer immunotherapeutics." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1844. http://dx.doi.org/10.1158/1538-7445.am2023-1844.

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Abstract There has been dramatic progress in the understanding of fundamental causes of cancer, giving rise to novel treatments which harness the power of the immune system to combat cancer progression. Despite this, no two cancers have the same pathogenesis and there is significant variation in patient response rates. Understanding mechanisms of carcinogenesis in model cell culture systems, such as aberrant signaling, as well as how tumor immunity can be initiated, retargeted or reinvigorated upon incorporation of the immune system will fuel drug discovery. High-Content Screening (HCS) platforms allow single-cell imaging analysis and are used to interrogate these models to enable drug development and understand mechanisms of action. They provide an opportunity to test novel cancer therapeutics in a translationally relevant setting that integrates primary immune effector function. Here we outline several macrophage-based HCS assays which allow assessment of therapeutics targeting;1) early aspects of immune cell activation 2) macrophage mitochondrial health 3) macrophage activation and re-polarization 4) immune cell infiltration and tumor killing. To test efficacy of drugs targeting immune signaling or activation, macrophages were treated with a canonical NF-ƙB activator +/- TCPA-1, a known inhibitor for benchmarking as a model therapeutic. Robust NF-ƙB translocation was observed and reduced in the presence of TCPA-1 rendering this an appropriate assay to screen therapeutic cytokines or TLR agonists activating NF-ƙB signaling. A macrophage inflammasome activation assay was developed to analyze levels of ASC and speck formation. CRID3i, an established inflammasome inhibitor was validated as a robust control therapeutic that prevented NLRP3 activation suggesting this is a relevant platform to assess cancer drug efficacy. Interrogating mitochondrial health and dynamics in primary macrophages is vital to understanding the impact of accumulating ROS species or metabolites in the tumor microenvironment. Assays modelling the effects of these molecules on macrophage polarization and activation as well as mitochondrial integrity were used to test macrophage repolarizing therapeutics, a key approach in immuno-oncology. Finally, a complex multi-cellular 3D spheroid tumor killing assay was optimized to model immune cell infiltration following exposure to IO-targeted therapeutics and robust enhancement of tumor killing was directly observed. Overall, these assays demonstrate the power of imaging in performing HCS to assess the efficacy and mechanisms of action of a range of IO-targeted therapeutics. This suite of assays is applicable to IO drug screens targeting macrophage function, immune cell activation and immune cell infiltration. Citation Format: Rebecca Roberts, Henry Leonard, Ilona Aylott, Douglas Best, Dan Rocca, Ben Thompson, Nunan Robert, Louise Brackenbury. Development of a high content screening (HCS) platform for novel cancer immunotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1844.

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Haque, Mohammad, Safnas Abdul Salam, Shawn McGinley, Haiching Ma, and jianghong Wu. "Abstract 6650: Cell-based assay to support development and characterization of new drugs in immuno-oncology." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6650. http://dx.doi.org/10.1158/1538-7445.am2023-6650.

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Abstract The years since 2009 have seen tremendous progress in unlocking the curative potential of the immune system for the treatment of cancer. Much of that revolution in immuno-oncology has been fueled by the clinical success of immune checkpoint inhibitors, targeting cytokines, antibody dependent cell cytotoxicity and complement dependent cytotoxicity via the T cell activation. Reaction biology has established state-of-art high throughput screening procedures for measuring the ability of new Biologics or compounds to activate T cells. Antibody Dependent Cell Cytotoxicity (ADCC), T cell activation assay (NFAT), immune checkpoint inhibitor assay (PD-1/PD-L1 blockade bioassay), cytokines activation assay and Complement Dependent Cytotoxicity (CDC) are commonly used for drug discovery industry. ADCC is a desirable mechanism for killing target cells using antibody-based drugs. T cell activation assay can be used for the discovery and development of novel biologics and cell therapies aimed at inducing, strengthening and/or engineering T cell response. Blocking of immune inhibitory receptors by their respective ligands on an adjacent cell inhibits TCR mediated proliferation, transcriptional activation and cytokines production. Biologics or compounds designed for measuring the stimulatory or inhibitory function of cytokines are promising in the field of immune oncology. Reaction Biology developed biochemical assays for PD-1/PD-L1, CTLA4/CD80 and CTLA4/CD86 to screen immune checkpoint inhibitors. All of these screening procedures and experimental methods will help to identify new therapeutic biologics or compounds for drug discovery in immune-oncology field. Citation Format: Mohammad Haque, Safnas Abdul Salam, Shawn McGinley, Haiching Ma, jianghong Wu. Cell-based assay to support development and characterization of new drugs in immuno-oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6650.

9

Saunders, Ute, and John F. Kearney. "Exosome-mediated B cell activation (36.11)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S14. http://dx.doi.org/10.4049/jimmunol.178.supp.36.11.

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Abstract The mature B cell population is divided into splenic follicular (FO) B, marginal zone (MZ) B and B1 B cells by phenotype, localization, and function. MZ B and B1 B cells participate in the early immune response against blood-borne T-independent (TI) antigens to bridge the temporal gap between the innate and adaptive immune response. We previously described the capture and transport of bacteria to the spleen by blood-derived CD11c immature dendritic cells (DCs), which are responsible for initiating immune responses to TI-2 antigens. However, the molecular basis of the DC-B cell interaction is complex, since supernatant (SN) from bacteria-primed DCs alone initiates antigen (Ag)-specific MZ B cell differentiation in vitro. Therefore, we propose that bacteria-primed DCs release factors able to initiate Ag-specific plasmablast generation. Recent findings that DCs secrete exosomes, which have the ability to stimulate T-dependent (TD) immune responses, support our hypothesis. To determine whether exosomes are involved in TI immune responses, we isolated exosomes from SN of bacteria-primed DCs (BMDC) and cocultured them with splenic B cells from M167 heavy chain transgenic (tg) mice expressing a dominant B cell clone, reactive with phosphorylcholine (PC). Using this system, we show that exosomes isolated from SN of Streptococcus pneumoniae primed BMDCs can specifically activate the M167 B cell clones, but not B cells from hen-egg-lysozyme (HEL)-specific MD4 tg B cell mice. These results suggest an involvement of exosomes in Ag-specific MZ B cell differentiation.

10

Trott, Daniel W., and David G. Harrison. "The immune system in hypertension." Advances in Physiology Education 38, no. 1 (March 2014): 20–24. http://dx.doi.org/10.1152/advan.00063.2013.

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While hypertension has predominantly been attributed to perturbations of the vasculature, kidney, and central nervous system, research for almost 50 yr has shown that the immune system also contributes to this disease. Inflammatory cells accumulate in the kidneys and vasculature of humans and experimental animals with hypertension and likely contribute to end-organ damage. We and others have shown that mice lacking adaptive immune cells, including recombinase-activating gene-deficient mice and rats and mice with severe combined immunodeficiency have blunted hypertension to stimuli such as ANG II, high salt, and norepinephrine. Adoptive transfer of T cells restores the blood pressure response to these stimuli. Agonistic antibodies to the ANG II receptor, produced by B cells, contribute to hypertension in experimental models of preeclampsia. The central nervous system seems important in immune cell activation, because lesions in the anteroventral third ventricle block hypertension and T cell activation in response to ANG II. Likewise, genetic manipulation of reactive oxygen species in the subfornical organ modulates both hypertension and immune cell activation. Current evidence indicates that the production of cytokines, including tumor necrosis factor-α, interleukin-17, and interleukin-6, contribute to hypertension, likely via effects on both the kidney and vasculature. In addition, the innate immune system also appears to contribute to hypertension. We propose a working hypothesis linking the sympathetic nervous system, immune cells, production of cytokines, and, ultimately, vascular and renal dysfunction, leading to the augmentation of hypertension. Studies of immune cell activation will clearly be useful in understanding this common yet complex disease.

11

Walsh, Alex J., Katie Mueller, Isabel Jones, Tiffany M. Heaster, Krishanu Saha, and Melissa C. Skala. "Autofluorescence Imaging of T cell Activation." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 120.13. http://dx.doi.org/10.4049/jimmunol.200.supp.120.13.

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Abstract T cells can have different activities based on receptor expression and cytokine production. Current methods to classify and assess immune cell behavior include flow cytometry and immunohistochemistry, which require immune cell labeling and tissue fixation. A non-invasive method for determining T cell behavior is needed to study immune cell behaviors in tumors and evaluate novel immunotherapies. Activated T cells require high rates of glycolysis to maintain immune activities. Therefore, we are developing optical metabolic imaging (OMI) to assess the metabolic profile of T cell subtypes and activation states using cells isolated from human blood. OMI probes the fluorescence intensity and lifetime of the metabolic coenzymes NAD(P)H and FAD, to quantitate the redox state of the cell through the optical redox ratio (NAD(P)H fluorescence intensity divided by the sum of NAD(P)H and FAD fluorescence intensity) and co-enzyme binding. Our results show that the optical redox ratio is increased in activated populations of unsorted T cells, and of CD8+ T cells, consistently across four different donors. Single-cell analysis of the unsorted, unactivated T cell populations revealed a small portion of cells in an activated state. Inter-donor heterogeneity highlights the variability of immune responses between patients. These results indicate that OMI is a powerful tool for assessing T cell subtype and behavior. OMI utilizes the autofluorescent properties of NAD(P)H and FAD, and thus is contrast agent free, non-damaging, and requires no genetic manipulation. Therefore, OMI can be used to image T cell interactions with tumors in time-course studies of tumor development or assess the efficacy of immunotherapy.

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Crawford, Keith, Aleksandra Stark, Betsy Kitchens, Kerry Sternheim, Vassilios Pantazopoulos, Ellen Triantafellow, Zhigang Wang, et al. "CD2 engagement induces dendritic cell activation: implications for immune surveillance and T-cell activation." Blood 102, no. 5 (September 1, 2003): 1745–52. http://dx.doi.org/10.1182/blood-2002-07-2206.

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Abstract We have shown previously that primary dendritic cells and monocytes express equal levels of CD14 but are distinguishable by the presence of CD2 on dendritic cells. CD2 is known to mediate the activation of T and natural killer (NK) cells through its interaction with CD58. CD2 epitopes recognized by anti-T111, -T112, and -T113 monoclonal antibodies (mAbs) are present on dendritic cells. Here we show that CD2 engagement significantly increases class II, costimulatory (CD40, CD80, CD86), adhesion (CD54, CD58), and CCR7 molecule expression on primary dendritic cells. Conversely, minimal or no change in the expression of the above antigens occurs on monocyte-derived dendritic cells, because these molecules are already maximally expressed. However, both kinds of dendritic cells release interleukin-1β (IL-1β) and IL-12 after CD2 engagement. Lastly, interference with dendritic cell CD2–T-cell CD58 engagement decreases naive CD4+CD45RA+ T-cell proliferation. Collectively, our results suggest another role of the CD2-CD58 pathway that allows nonimmune and immune cells to interact directly with dendritic cells and initiate innate and adaptive immune responses.

13

Breckpot, Karine. "Strategies to enhance immune cell activation & cancer cell killing." Immuno Oncology Insights 11, no. 03 (December 15, 2022): 553–59. http://dx.doi.org/10.18609/ioi.2022.056.

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14

Wachowicz, Katarzyna, та Gottfried Baier. "Protein kinase Cθ: the pleiotropic T-cell signalling intermediate". Biochemical Society Transactions 42, № 6 (17 листопада 2014): 1512–18. http://dx.doi.org/10.1042/bst20140179.

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Activating as well as inhibitory circuits tightly regulate T-cell activation thresholds and effector differentiation processes enabling proper immune response outcomes. Recently, an additional molecular link between T-cell receptor signalling and CD4+ Th17 cell skewing has been reported, namely that protein kinase C (PKC) θ critically regulates Th17/Th1 phenotypic differentiation and plasticity in CD4+ T-cells by selectively acting as a ‘reprogramming element’ that suppresses Th1-typical genes during Th17-mediated immune activation in order to stabilize a Th17 cell phenotype.

15

Shajahan, Thamrook s., Shaiju S Dharan, and Merlin Nj. "A review on immune checkpoint blockage therapy." International Journal of Research in Hospital and Clinical Pharmacy 2, no. 1 (February 13, 2020): 12–17. http://dx.doi.org/10.33974/ijrhcp.v2i1.159.

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Activating the immune system to eliminate cancer cells and produce clinically relevant response has been a long standing goal of cancer research. Most promising therapeutic approaches of activating antitumor immunity include immune checkpoint inhibitors. Our immune system protect us from disease, killing bacteria and virus. One main type of immune cell called T-cells. T-cells have protein that turn it off. These are called checkpoint. Immune checkpoint are accessory molecules that either promote or inhibit T-cell activation. Checkpoint inhibitor are a type of immunotherapy. They block protein that stops the immune system from attacking the cancer cells. Checkpoint inhibitor are a type of monoclonal antibody or targeted treatment. Immune system cells, such as T-cells and Antigen presenting cells (APCs), defend and protect the body. Immune system play an important role in controlling and eradicating cancer. Cytotoxic T lymphocytes associated protein 4(CTLA-4) and Programmed cell dealth protein (PD-1) are checkpoint protein which is the negative regulation of T-cell immune function. Inhibition of the target, results in increased activation of immune system.

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Ayash-Rashkovsky, Mila, Zvi Bentwich, and Gadi Borkow. "TLR9 expression is related to immune activation but is impaired in individuals with chronic immune activation." International Journal of Biochemistry & Cell Biology 37, no. 11 (November 2005): 2380–94. http://dx.doi.org/10.1016/j.biocel.2005.05.012.

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Zhang, Gao-Hong, Run-Dong Wu, Hong-Yi Zheng, Xiao-Liang Zhang, Ming-Xu Zhang, Ren-Rong Tian, Guang-Ming Liu, Wei Pang, and Yong-Tang Zheng. "Lipopolysaccharide Increases Immune Activation and Alters T Cell Homeostasis in SHIVB’WHUChronically Infected Chinese Rhesus Macaque." Journal of Immunology Research 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/202738.

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Immune activation plays a significant role in the disease progression of HIV. Microbial products, especially bacterial lipopolysaccharide (LPS), contribute to immune activation. Increasing evidence indicates that T lymphocyte homeostasis disruptions are associated with immune activation. However, the mechanism by which LPS affects disruption of immune response is still not fully understood. Chronically SHIVB’WHU-infected Chinese rhesus macaques received 50 μg/kg body weight LPS in this study. LPS administration affected the virus/host equilibrium by elevating the levels of viral replication and activating T lymphocytes. LPS induced upregulation of CD8+naïve T cells and downregulated the number of CD4+and CD8+T effector memory cells. The downregulated effector memory cells are associated with a lower frequency of monofunctional and polyfunctional cells, and an upregulated programmed cell death-1 (PD-1) expression on CD4+and CD8+T cells was observed in monkeys after LPS stimulation. Our data provide new insights into the function of LPS in the immune activation in SHIV/HIV infection.

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Henneke, P., I. Osmers, K. Bauer, N. Lamping, H. T. Versmold, and R. R. Schumann. "CD14-dependent immune cell activation in preterm infants." Pediatric Research 45, no. 6 (June 1999): 898. http://dx.doi.org/10.1203/00006450-199906000-00088.

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Pearce, Erika L., and Edward J. Pearce. "Metabolic Pathways in Immune Cell Activation and Quiescence." Immunity 38, no. 4 (April 2013): 633–43. http://dx.doi.org/10.1016/j.immuni.2013.04.005.

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Deane, Jonathan A., and David A. Fruman. "Phosphoinositide3-Kinase: Diverse Roles in Immune Cell Activation." Annual Review of Immunology 22, no. 1 (April 2004): 563–98. http://dx.doi.org/10.1146/annurev.immunol.22.012703.104721.

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Goldeck, David, Claudia Schulte, Marcia Cristina Teixeira dos Santos, Dieter Scheller, Lilly Öttinger, Graham Pawelec, Christian Deuschle, Daniela Berg, Andre Nogueira da Costa, and Walter Maetzler. "Higher Frequencies of T-Cells Expressing NK-Cell Markers and Chemokine Receptors in Parkinson’s Disease." Journal of Ageing and Longevity 3, no. 1 (December 22, 2022): 1–10. http://dx.doi.org/10.3390/jal3010001.

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Immune cells are thought to be involved in a destructive cycle of sterile cerebral inflammatory responses in neurodegenerative diseases such as Parkinson’s Disease (PD). Despite their peripheral origin, immune cells may enter the CNS due to impaired blood–brain barrier function and may potentially contribute to neuronal damage. Hence, specific characteristics of peripherally activated immune cells could help in understanding neurodegeneration in PD and could potentially serve as accessible disease markers. To investigate immune cell activation status, the expression of receptors for cell surface molecules CD161, NKG2A, NKG2C and NKG2D as well as chemokine receptors CCR6, CXCR2, CXCR3 and CCR5 associated with neurodegenerative diseases was investigated. The frequencies of peripheral CD8+ T-cells expressing the inhibitory and activating receptors NKG2A and NKG2C, and the activating receptor NKG2D were higher in PD patients than in healthy matched controls. The frequencies of NKG2C+CD8− cells were also higher, whereas the frequencies of CD161+ cells were not significantly different. Of the chemokine receptor-expressing cells, only the proportion of CD4−CD56+CCR5+ T-cells was higher in PD patients than in the controls. These observations support the hypothesis that an imbalance in the activation state of T-cells plays a role in the pathological processes of PD and suggest that peripheral blood immune cell phenotypes could be specific early markers for inflammation in PD.

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Le, Chau Thuy Tien, So Yeon Ahn, Sang-Moo Kang, and Eun-Ju Ko. "Functional NK Cell Activation by Ovalbumin Immunization with a Monophosphoryl Lipid A and Poly I:C Combination Adjuvant Promoted Dendritic Cell Maturation." Vaccines 9, no. 10 (September 23, 2021): 1061. http://dx.doi.org/10.3390/vaccines9101061.

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Natural killer (NK) cells are one of the types of innate immune cells to remove pathogen-infected cells and modulate inflammatory immune responses. Recent studies have revealed that NK cells could enhance vaccine efficacy by coordinating the innate and adaptive immune responses. In this study, we have evaluated the efficacy of intranasal ovalbumin (OVA) immunization with a monophosphoryl lipid A (MPL) and polyriboinosinic polyribocytidylic acid (poly I:C) combination adjuvant in promoting NK cell recruitment, differentiation, and activation. The frequencies of NK cells were positively correlated with those of dendritic cells (DCs) at the site of immunization. Moreover, the activated NK cells and DCs by the MPL + poly I:C combination adjuvant induced activations of each other cells in vitro. Taken together, this study suggested that the MPL and poly I:C combination adjuvant in OVA vaccination mediated NK cell activation and cellular crosstalk between NK cells and DCs, suggesting a promising vaccine adjuvant candidate for promoting cellular immune responses.

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Shi, Xiaoshan, Imteaz Siddique, Margaret Nakamoto, and Stefanie Mortimer. "Simultaneous mRNA, protein, and immune repertoire profiling of antigen-specific T cells by single cell sequencing." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 246.17. http://dx.doi.org/10.4049/jimmunol.204.supp.246.17.

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Abstract High-throughput single cell RNA-seq (scRNA-seq) has transformed our understanding of complex and heterogenous immune populations. New advances in scRNA-seq are expanding the molecules that can be profiled at the single cell level, such as oligo-conjugated antibody technologies that enable protein expression profiling alongside mRNA. Although the ability to sequence the immune repertoire can provide crucial insights into understanding the complexities of the adaptive immune system and advancing discoveries in immuno-oncology, the ability to extract this information from single cells requires new technology to profile regions of the mRNA that are missed by conventional 3′ scRNA-seq. In this study we utilized an ex vivo antigen stimulation system to measure antigen-specific T-cell activation and clonal amplification. Stimulated T cells from two donors were loaded onto the BD Rhapsody™ Single-Cell Analysis System to extract immune repertoire information in addition to gene and protein expression information from the same cells. In a single workflow, we profiled a panel of 400 mRNA targets, 20 BD® AbSeq protein markers associated with different status of T-cell activation, and the hypervariable region of T-cell receptors at the single cell resolution. The study is a proof of concept of combining mRNA, protein and immune repertoire analysis at the single cell level to deconvolute the heterogeneity and different activation of stimulated T cells. For Research Use Only. Not for use in diagnostic or therapeutic procedures. BD, the BD Logo, and Rhapsody are trademarks of Becton, Dickinson and Company or its affiliates. © 2019 BD. All rights reserved.

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Sullivan, Brian M., and Laurent Coscoy. "Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein." Journal of Virology 82, no. 2 (October 31, 2007): 602–8. http://dx.doi.org/10.1128/jvi.01571-07.

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ABSTRACT We have performed a screen aimed at identifying human herpesvirus 6 (HHV-6)-encoded proteins that modulate immune recognition. Here we show that the U24 protein encoded by HHV-6 variant A downregulates cell surface expression of the T-cell receptor (TCR)/CD3 complex, a complex essential to T-cell activation and the generation of an immune adaptive response. In the presence of U24, the TCR/CD3 complex is endocytosed but is not recycled back to the plasma membrane. Instead, it accumulates in early and late endosomes. Interestingly, whereas CD3 downregulation from the cell surface is normally associated with T-cell activation, U24 downregulates CD3 independently of T-cell activation. Moreover, we found that U24-expressing T cells are resistant to activation by antigen-presenting cells. HHV-6 has evolved a unique mechanism of inhibition of T-cell activation that may impair the establishment of an adaptive immune response. Furthermore, lymphocyte activation creates an environment favorable to the reactivation and replication of lymphotropic herpesviruses. Thus, by inhibiting T-cell activation, HHV-6 might limit its reactivation and thus minimize immune recognition.

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Yin, Xiangyun, Shuting Chen, and Stephanie C. Eisenbarth. "Dendritic Cell Regulation of T Helper Cells." Annual Review of Immunology 39, no. 1 (April 26, 2021): 759–90. http://dx.doi.org/10.1146/annurev-immunol-101819-025146.

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As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4+ T helper (Th) cell differentiation outcomes, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation.

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Cekic, Caglar, Imran Akdemir, Altay Koyas, Merve Kayhan, and Ali Can Savas. "Molecular mechanisms for adenosine regulation of helper T cell activation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 52.22. http://dx.doi.org/10.4049/jimmunol.198.supp.52.22.

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Abstract Polarization of T helper subsets into different functional phenotypes strongly affects the progression of immune-related diseases. One of the hallmarks of immune cell activation and inflammation is the elevation of extracellular adenosine and increased expression of adenosine A2A receptors in activated immune cells. Adenosine strongly inhibits activation of helper T cells by elevating cAMP concentrations, which activate PKA and EPAC proteins to regulate cellular responses. Here we showed that adenosine strongly inhibits T cell accumulation rather than differentiating into functional subsets in the presence of polarizing conditions. Different aspects of adenosine mediated T cell suppression were phenocopied by specific activation of PKA and/or EPAC pathways. Adenosine can suppress phospho-activation of Akt pathway to promote T cell quiescence and to inhibit immediate downstream events after TCR stimulation. One of the targets for Akt is Foxo1. Foxo1 is known to suppress T cell proliferation. Our results showed that adenosine receptor stimulation reduced inhibitory phosphorylation of Foxo1 downstream of Akt. Foxo1 inhibitor, AS1842856, completely reversed the inhibition of T cell accumulation by adenosine signaling. Our results suggest that adenosine by activating PKA and/or EPAC pathways and by sustaining Foxo1 activation suppresses T cell activation and accumulation. These findings have important implications to develop novel interventions to regulate helper T cell responses in different pathological conditions.

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Marolda, Alessandra, Kerstin Hünniger, Sarah Böttcher, Wolfgang Vivas, Jürgen Löffler, Marc Thilo Figge, and Oliver Kurzai. "Candida Species-Dependent Release of IL-12 by Dendritic Cells Induces Different Levels of NK Cell Stimulation." Journal of Infectious Diseases 221, no. 12 (January 29, 2020): 2060–71. http://dx.doi.org/10.1093/infdis/jiaa035.

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Abstract Background Candida albicans and Candida glabrata are the 2 most prevalent Candida species causing bloodstream infections. Patterns of innate immune activation triggered by the 2 fungi differ considerably. Methods To analyze human natural killer (NK) cell activation by both species, we performed ex vivo whole-blood infection assays and confrontation assays with primary human NK cells. Results C. albicans was a stronger activator for isolated human NK cells than C. glabrata. In contrast, activation of blood NK cells, characterized by an upregulated surface exposure of early activation antigen CD69 and death receptor ligand TRAIL, as well as interferon-γ (IFN-γ) secretion, was more pronounced during C. glabrata infection. NK cell activation in blood is mediated by humoral mediators released by other immune cells and does not depend on direct activation by fungal cells. Cross-talk between Candida-confronted monocyte-derived dendritic cells (moDC) and NK cells resulted in the same NK activation phenotype as NK cells in human blood. Blocking experiments and cytokine substitution identified interleukin-12 as a critical mediator in regulation of primary NK cells by moDC. Conclusions Activation of human NK cells in response to Candida in human blood mainly occurs indirectly by mediators released from monocytic cells.

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Pollak, Daniela D., and Ulrike Weber-Stadlbauer. "Transgenerational consequences of maternal immune activation." Seminars in Cell & Developmental Biology 97 (January 2020): 181–88. http://dx.doi.org/10.1016/j.semcdb.2019.06.006.

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Wolfert, Margreet A., and Geert-Jan Boons. "Adaptive immune activation: glycosylation does matter." Nature Chemical Biology 9, no. 12 (November 14, 2013): 776–84. http://dx.doi.org/10.1038/nchembio.1403.

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Srpan, Katja, Ashley Ambrose, Alexandros Karampatzakis, Mezida Saeed, Adam N. R. Cartwright, Karolin Guldevall, Gabriela Dos Santos Cruz De Matos, Björn Önfelt, and Daniel M. Davis. "Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells." Journal of Cell Biology 217, no. 9 (July 2, 2018): 3267–83. http://dx.doi.org/10.1083/jcb.201712085.

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Natural Killer (NK) cells can engage multiple virally infected or tumor cells sequentially and deliver perforin for cytolytic killing of these targets. Using microscopy to visualize degranulation from individual NK cells, we found that repeated activation via the Fc receptor CD16 decreased the amount of perforin secreted. However, perforin secretion was restored upon subsequent activation via a different activating receptor, NKG2D. Repeated stimulation via NKG2D also decreased perforin secretion, but this was not rescued by stimulation via CD16. These different outcomes of sequential stimulation could be accounted for by shedding of CD16 being triggered by cellular activation. The use of pharmacological inhibitors and NK cells transfected to express a noncleavable form of CD16 revealed that CD16 shedding also increased NK cell motility and facilitated detachment of NK cells from target cells. Disassembly of the immune synapse caused by CD16 shedding aided NK cell survival and boosted serial engagement of target cells. Thus, counterintuitively, shedding of CD16 may positively impact immune responses.

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Krämer, Benjamin, Moritz Kebschull, Michael Nowak, Ryan T. Demmer, Manuela Haupt, Christian Körner, Sven Perner, Søren Jepsen, Jacob Nattermann, and Panos N. Papapanou. "Role of the NK Cell-Activating Receptor CRACC in Periodontitis." Infection and Immunity 81, no. 3 (December 17, 2012): 690–96. http://dx.doi.org/10.1128/iai.00895-12.

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ABSTRACTPeriodontitis is a highly prevalent, biofilm-mediated chronic inflammatory disease that results in the loss of the tooth-supporting tissues. It features two major clinical entities: chronic periodontitis, which is more common, and aggressive periodontitis, which usually has an early onset and a rapid progression. Natural killer (NK) cells are a distinct subgroup of lymphocytes that play a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. However, the exact mechanisms of their activation and their role in the pathophysiology of periodontitis are elusive. Here, we show that the predominant NK cell-activating molecule in periodontitis is CD2-like receptor activating cytotoxic cells (CRACC). We show that CRACC induction was significantly more pronounced in aggressive than chronic periodontitis and correlated positively with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activationin vivo. We delineate howAggregatibacter actinomycetemcomitans, an oral pathogen that is causally associated with aggressive periodontitis, indirectly induces CRACC on NK cells via activation of dendritic cells and subsequent interleukin 12 (IL-12) signaling. In contrast, we demonstrate that fimbriae fromPorphyromonas gingivalis, a principal pathogen in chronic periodontitis, actively attenuate CRACC induction on NK cells. Our data suggest an involvement of CRACC-mediated NK cell activation in periodontal tissue destruction and point to a plausible distinction in the pathobiology of aggressive and chronic periodontitis that may help explain the accelerated tissue destruction in aggressive periodontitis.

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Tran, Charles W., Matthew J. Gold, Carlos Garcia-Batres, Kelly Tai, Alisha R. Elford, Megan E. Himmel, Andrew J. Elia, and Pamela S. Ohashi. "Hypoxia-inducible factor 1 alpha limits dendritic cell stimulation of CD8 T cell immunity." PLOS ONE 15, no. 12 (December 31, 2020): e0244366. http://dx.doi.org/10.1371/journal.pone.0244366.

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Dendritic cells are sentinels of the immune system and represent a key cell in the activation of the adaptive immune response. Hypoxia-inducible factor 1 alpha (HIF-1α)–a crucial oxygen sensor stabilized during hypoxic conditions–has been shown to have both activating and inhibitory effects in immune cells in a context- and cell-dependent manner. Previous studies have demonstrated that in some immune cell types, HIF-1α serves a pro-inflammatory role. Genetic deletion of HIF-1α in macrophages has been reported to reduce their pro-inflammatory function. In contrast, loss of HIF-1α enhanced the pro-inflammatory activity of dendritic cells in a bacterial infection model. In this study, we aimed to further clarify the effects of HIF-1α in dendritic cells. Constitutive expression of HIF-1α resulted in diminished immunostimulatory capacity of dendritic cells in vivo, while conditional deletion of HIF-1α in dendritic cells enhanced their ability to induce a cytotoxic T cell response. HIF-1α-expressing dendritic cells demonstrated increased production of inhibitory mediators including IL-10, iNOS and VEGF, which correlated with their reduced capacity to drive effector CD8+ T cell function. Altogether, these data reveal that HIF-1α can promote the anti-inflammatory functions of dendritic cells and provides insight into dysfunctional immune responses in the context of HIF-1α activation.

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Willems, Kristen, Madelyn Schmidt, and Robert Woodland. "Pim kinases significantly impact humoral immune responses (IRM12P.648)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 133.7. http://dx.doi.org/10.4049/jimmunol.194.supp.133.7.

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Abstract The Provirus Integration site for Moloney murine leukemia virus (Pim) family of oncogenic serine/threonine kinases regulates a variety of metabolic functions in hematopoietic cells and lymphocytes. We examined the importance of Pim kinases in B cell activation following antigen stimulation. Humoral immune responses were significantly impaired in Pim 1 and 2 deficient mice (Pim 1-/-2-/-) T cell dependent responses were compromised while T cell independent type 1 and 2 antigen responses were virtually absent. Humoral deficiencies were owing to reduced production of antibody secreting cells due to the diminished induction of BLIMP-1 expression. The central role of Pim in these responses is consistent with our observation that Pims are induced downstream of multiple B cell activation receptors including CD40, BCR, and TLR4. We suggest that Pim 1 and 2 dependent signaling pathways are involved in B cell activation and their loss requires increased signaling through other pathways to reach an activation threshold. This hypothesis is further supported by the initial higher affinity of BCRs on Pim deficient B cells activated in a TD response and their inability to proliferate or undergo isotype switching in culture at the same rate as WT B cells when activator concentrations are decreased. Taken together, these data demonstrate a critical role for Pim kinases in affinity maturation, isotype switching, proliferation and the production of antibody secreting cells by B lymphocytes. .

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Coito, Ana J., Maria De Sousa, and Jerzy W. Kupiec-Weglinski. "Fibronectin in Immune Responses in Organ Transplant Recipients." Developmental Immunology 7, no. 2-4 (2000): 239–48. http://dx.doi.org/10.1155/2000/98187.

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The immune response to an organ allograft involves perpetuation of T cell infiltration and activation. Advances in understanding the mechanisms of T cell activation have placed particular emphasis on the interactions between the T-cell receptor and antigen presenting cells, with little reference to the fact that in vivo activation occurs in the physical context of extracellular matrix proteins (ECM). Indeed, the possibility that ECM proteins may have a determining role in lymphocyte adhesion and tissue localization and function is now becoming more appreciated in view of growing evidence indicating that integrins and other T cell antigens bind ECM components, with some of these components exerting synergistic effects on T- cell activation. This review focuses on the importance of interactions between lymphocytes and fibronectin, a prominent ECM component, for cell migration and function in organ allograft recipients. It explores novel therapeutic approaches based on the assumption that fibronectin represents an active element in the process of T cell activation in the immune cascade triggered by organ transplantation.

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Nikolajczyk, Barbara, Min Zhu, Qiang Xiao, Ramya Kuchibhatla, and Caroline Apovian. "An obesity-associated cytokine profile for immune cell differentiation and activation (HEM4P.253)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 117.4. http://dx.doi.org/10.4049/jimmunol.192.supp.117.4.

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Abstract Immune cells are dominant sources of the obesity-associated inflammation that predisposes type 2 diabetes (T2D), but triggers of immune cell hyper-responsiveness in obesity/T2D are poorly understood. T cells are key sources of cytokines that promote immune cell differentiation/activation, although T cells generally require contact with other immune cells to produce obesity-associated amounts of cytokines. To test the possibility that obesity associates with cytokine changes that impact immune cell differentiation/activation, we stimulated T cells from lean, obese non-diabetic (ND), or obese pre-diabetic (PD; HbA1c 5.6-6.5) subjects in the context of PBMCs and quantitated cytokines with the Milliplex Human High Sensitivity T Cell Panel. Samples from ND and PD subjects produced more T cell/Th1-supportive IL-2, IL-7 and IL-12p70, myeloid-supportive GM-CSF, and B cell-supportive IL-21 compared to samples from leans. In contrast, anti-inflammatory IL-10 was highest in samples from leans. Based on the anti-inflammatory actions of the T2D drug metformin, we also measured cytokine production by samples from PD subjects that were taking metformin. Metformin partially restored IL-10 production in samples from PD subjects, but had no impact on immune cell-activating cytokines. We conclude that obesity associates with inflammation due to over-expression of cytokines that support immune cell differentiation/activation, and that anti-inflammatory action of in vivo metformin is limited.

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Harlé, Guillaume, Camille Kowalski, Laure Garnier, and Stéphanie Hugues. "Lymph Node Stromal Cells: Mapmakers of T Cell Immunity." International Journal of Molecular Sciences 21, no. 20 (October 21, 2020): 7785. http://dx.doi.org/10.3390/ijms21207785.

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Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell maturation, migration and activation. Recent characterizations of SCs have expanded our understanding of their heterogeneity and suggested a functional specialization of distinct SC subsets, further modulated by the microenvironment. Lymph node SCs (LNSCs) have been shown to be particularly important in maintaining immune homeostasis and T cell tolerance. Under inflammation situations, such as viral infections or tumor development, SCs undergo profound changes in their numbers and phenotype and play important roles in contributing to either the activation or the control of T cell immunity. In this review, we highlight the role of SCs located in LNs in shaping peripheral T cell responses in different immune contexts, such as autoimmunity, viral and cancer immunity.

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Wang, Li, Isabelle LeMercier, Arief Suriawinata, Wenna Chen, Jiannan Li, and Randolph Noelle. "VISTA deficiency synergizes with a non-redundant immune checkpoint pathway and leads to enhanced immune activation (IRM10P.744)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 129.11. http://dx.doi.org/10.4049/jimmunol.192.supp.129.11.

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Abstract V-domain Ig suppressor of T cell activation (VISTA) is a novel negative checkpoint ligand that suppresses T-cell mediated immune responses. Previous studies using VISTA-neutralizing monoclonal antibody show that VISTA-blockade enhances T cell-activation in an inflammatory disease model EAE, as well as in murine tumor models. Current study describes a comprehensive characterization of VISTA knockout (KO) mice. We show that despite the apparent normal hematopoietic development in young ko mice, VISTA genetic deficiency leads to a pro-inflammatory phenotype in aged animals, as well as enhanced T-cell activation in response to acute antigen immunization. In addition, we show that VISTA deficiency significantly enhanced disease development in a spontaneous model of autoimmune disease, which is correlated with the spontaneous activation of auto-antigen specific CD4+ T cells. Lastly, when combined with the genetic deficiency of another checkpoint molecule, synergistic or additive immune activation was observed.

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Dufort, Fay, Christopher J. Leitheiser, Kathleen Ho, Tucker Ezell, Alexandra Rezvaya, Peter Brown, Liuhong Chen, et al. "Abstract 1806: Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r)." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1806. http://dx.doi.org/10.1158/1538-7445.am2023-1806.

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Abstract The tumor specific activation of natural killer (NK) cells with Bicycles is an area of active investigation in immune oncology. NK cells are highly responsive immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Bicycles are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle platform technology to discover and evaluate a new class of fully synthetic molecules termed NK tumor immune cell agonists (NK-TICA®). The NK-TICA® consists of chemically coupled Bicycles® that bind specifically to the key activating receptor, NKp46, and to tumor antigens, that results in highly potent, antigen-dependent receptor activation and NK cell activation. We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA® compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner. In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle NK-TICA® as a multifunctional immune cell engager will promote the modulation of NK cells, as well as the infiltration and anti-tumor activity of NK cells in solid tumors. Citation Format: Fay Dufort, Christopher J. Leitheiser, Kathleen Ho, Tucker Ezell, Alexandra Rezvaya, Peter Brown, Liuhong Chen, Philip Brandish, Kevin McDonnell, Michael Skynner, Nicholas Keen. Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1806.

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McGarry, Sage V., Liu Yu, Dina Cruickshank, Ifeanyi Iloba, and Gitte S. Jensen. "Immune Activation by a Nutraceutical Blend: Rapid Increase in Immune-Modulating Cytokines, Followed by Induction of Anti-Inflammatory and Restorative Biomarkers." Nutraceuticals 4, no. 1 (January 2, 2024): 35–49. http://dx.doi.org/10.3390/nutraceuticals4010003.

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Immune cells express Pattern Recognition Receptors (PRRs) to recognize potentially pathogenic microbial forms. Nutraceutical compounds can induce immune cell activation through PRRs. The nutraceutical immune blend (IB), QuickStart™, contains botanical and yeast-derived ligands for PRRs, along with vitamin C and zinc. We evaluated immune-activating effects of the IB and its ingredients in vitro. Human peripheral blood mononuclear cells were treated with either the IB or single ingredients: elderberry extract, the proprietary Saccharomyces cerevisiae fermentate EpiCor™ (Sacc), the plant-based hemicellulose preparation Natramune (PDS-2865)™ (Hemi), vitamin C (VitC), or zinc gluconate (Zinc). The IB triggered sequential waves of immune activation. Initial cytokine induction by the IB at 2 h involved the immune-activating cytokines IL-6, IL-8, MIP-1α, and TNF-α, and the stem cell-mobilizing growth factor G-CSF, as did Sacc and Hemi. The 24 h immune-activation by the IB included increases in IL-1β, IL-17A, IP-10, GM-CSF, Basis FGF, PDGF-BB, and the anti-inflammatory cytokine IL-10. Increased CD69 expression by the IB was also seen for VitC and Sacc. Increased CD25 expression by the IB on monocytes was also seen for Sacc. The IB triggered rapid immune activating events of higher magnitude than the single ingredients, involving immune-activating cytokines and restorative growth factors. Clinical research is warranted to evaluate rapid immune-modulating events upon consumption.

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Luxembourg, A. T., and N. R. Cooper. "T cell-dependent, B cell-activating properties of antibody-coated small latex beads. A new model for B cell activation." Journal of Immunology 153, no. 2 (July 15, 1994): 604–14. http://dx.doi.org/10.4049/jimmunol.153.2.604.

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Abstract We have developed a new model to study B cell activation induced by complex particulate Ag, immune complexes, and viruses. As the surrogate for such Ag, we have used 100-nm fluorescent latex beads bearing mAb to IgM and IgD. Anti-IgM- and anti-IgD-coated small latex beads bind readily to tonsil resting B cells and induce homotypic B cell aggregation. Aggregation induced by anti-IgM-coated beads but not by anti-IgD-coated beads was massively enhanced by IL-2 and IL-4. Anti-IgM- and anti-IgD-coated beads increased (4- to 12-fold) c-fos and c-myc mRNA levels in resting B cells in a dose-dependent manner; this increase was tyrosine kinase dependent. Anti-IgM- and anti-IgD-coated beads were mitogenic for resting B cells, but unlike other B cell activation models, mitogenesis was absolutely dependent on the presence of IL-2 or IL-4. Finally, anti-IgM-coated beads but not anti-IgD-coated beads were internalized as single beads into small, thin-walled endocytic vesicles; internalization was absolutely dependent on the presence of IL-4. Binding and internalization can be readily quantified because the beads are fluorescent. This model can also be used to study the functions of other cell surface molecules that modulate Ag-specific B cell immune responses. It will also be used for examining multiple aspects of T-B cell interactions during immune responses and Ag processing because of the dependence on T cell factors for B cell activation, coupled with the finding that the Ab-coated beads are internalized.

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Holderness, Jeff, Brett Freedman, Igor Schepetkin, Sharon Kemoli, Jodi Hedges, and Mark Jutila. "Innate immune responses to açaí polysaccharides (52.31)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 52.31. http://dx.doi.org/10.4049/jimmunol.186.supp.52.31.

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Abstract The açaí fruit has become a popular nutritional supplement with anecdotal claims of increasing immunity. Previous works by others show that the procyanidin fraction of this supplement induces immune activation. We expand upon this work to identify an endotoxin-free, purified polysaccharide fraction in Açaí fruit that can also stimulate immune responses. Treatment with Açaí polysaccharides results in activation of the innate immune system, particularly γδ T cell and monocyte cell activation. Responses include: TNFα, IL-6, and IL-10 cytokine production, γδ T cell activation (CD69/IL-2Rα expression), ROS production, as well as myeloid cell recruitment/activation and IL-12 secretion in the lung after i.t. delivery. This response to Açaí polysaccharide is at least partially mediated by the polysaccharide receptor, Dectin-1. Unlike fungal polysaccharide recognition, which typically utilizes TLR2 as a co-receptor, our studies suggest that the lung immune response to Açaí polysaccharides is TLR2-independent and instead may require TLR4.

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Monaco, Sara, Beate Jahraus, Yvonne Samstag, and Hilmar Bading. "Nuclear calcium is required for human T cell activation." Journal of Cell Biology 215, no. 2 (October 17, 2016): 231–43. http://dx.doi.org/10.1083/jcb.201602001.

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Calcium signals in stimulated T cells are generally considered single entities that merely trigger immune responses, whereas costimulatory events specify the type of reaction. Here we show that the “T cell calcium signal” is a composite signal harboring two distinct components that antagonistically control genomic programs underlying the immune response. Using human T cells from healthy individuals, we establish nuclear calcium as a key signal in human T cell adaptogenomics that drives T cell activation and is required for signaling to cyclic adenosine monophosphate response element–binding protein and the induction of CD25, CD69, interleukin-2, and γ-interferon. In the absence of nuclear calcium signaling, cytosolic calcium activating nuclear factor of activated T cells translocation directed the genomic response toward enhanced expression of genes that negatively modulate T cell activation and are associated with a hyporesponsive state. Thus, nuclear calcium controls the T cell fate decision between a proliferative immune response and tolerance. Modulators of nuclear calcium–driven transcription may be used to develop a new type of pro-tolerance immunosuppressive therapy.

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Chenchik, Alex, Michael Makhanov, Russell Darst, Tianbing Liu, and Lester Kobzik. "69 Immunophenotyping of TCR and BCR clonotypes." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A77. http://dx.doi.org/10.1136/jitc-2021-sitc2021.069.

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BackgroundT-cell receptor (TCR) and B-cell receptor (BCR) repertoire profiling holds great potential for understanding disease mechanisms and for the development of new therapeutics in infectious diseases, autoimmunity and in immuno-oncology. However, this potential could be greatly improved by combining information about receptor clonotypes with immuno-phenotypes of T and B cells.MethodsTo facilitate these studies, we developed a novel technology for combined profiling of all human TCR and BCR variable regions and phenotypic characterization of immune cells in bulk and at the single-cell level in PBMC and immune cell fraction samples. The developed TCR/BCR Immunophenotyping method involves multiplex RT-PCR amplification and sequencing of CDR3 regions of TCR and BCR genes and a set of the most informative T- and B-cell phenotyping genes. Bioinformatics analysis of NGS data allows profiling of TCR/BCR clonotypes, and identification of major immune cell subtypes and their activation status.ResultsData will be presented showing how combined TCR/BCR clonotype analysis combined with targeted expression profiling of immune cells can be applied for large-scale discovery of novel cell typing and activation biomarkers in several immune-responsive model systems.ConclusionsPreliminary studies demonstrate the assay has unparalleled throughput, sensitivity, and improved cost-effectiveness for high-throughput immunity biomarker discovery applications.

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Chang, J. Judy, and Marcus Altfeld. "TLR-mediated immune activation in HIV." Blood 113, no. 2 (January 8, 2009): 269–70. http://dx.doi.org/10.1182/blood-2008-10-184598.

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van Pul, Kim M., Ronald J. C. L. M. Vuylsteke, Monique T. A. de Beijer, Rieneke van de Ven, M. Petrousjka van den Tol, Hein B. A. C. Stockmann, and Tanja D. de Gruijl. "Breast cancer-induced immune suppression in the sentinel lymph node is effectively countered by CpG-B in conjunction with inhibition of the JAK2/STAT3 pathway." Journal for ImmunoTherapy of Cancer 8, no. 2 (October 2020): e000761. http://dx.doi.org/10.1136/jitc-2020-000761.

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BackgroundWe previously showed selectively hampered activation of lymph node-resident (LNR) dendritic cell (DC) subsets in the breast cancer (BrC) sentinel lymph node (SLN) to precede a state of profound T cell anergy. Reactivating these DC subsets by intratumoral delivery of the Toll-like receptor-9 (TLR9) agonist CpG-B could potentially offer a promising immune therapeutic strategy to combat this immune suppression and prevent disease spread. Unfortunately, CpG-B can limit its own immune stimulatory activity through direct TLR9-mediated activation of signal transducer and activator of transcription 3 (STAT3), pinpointed as a key regulator of immune suppression in the tumor microenvironment. Here, we have investigated whether in vitro exposure to CpG-B, with or without simultaneous inhibition of STAT3 signaling, could overcome immune suppression in BrC SLN.MethodsImmune modulatory effects of CpG-B (CPG7909) with or without the JAK2/STAT3 inhibitor (STAT3i) AG490 were assessed in ex vivo cultured BrC SLN-derived single-cell suspensions (N=29). Multiparameter flow cytometric analyses were conducted for DC and T cell subset characterization and assessment of (intracellular) cytokine profiles. T cell reactivity against the BrC-associated antigen Mammaglobin-A was determined by means of interferon-γ ELISPOT assay.ResultsAlthough CpG-B alone induced activation of all DC subsets, combined inhibition of the JAK2/STAT3 pathway resulted in superior DC maturation (ie, increased CD83 expression), with most profound activation and maturation of LNR DC subsets. Furthermore, combined CpG-B and JAK2/STAT3 inhibition promoted Th1 skewing by counterbalancing the CpG-induced Th2/regulatory T cell response and significantly enhanced Mammaglobin-A specific T cell reactivity.ConclusionEx vivo immune modulation of the SLN by CpG-B and simultaneous JAK2/STAT3 inhibition can effectively overcome BrC-induced immune suppression by preferential activation of LNR DC, ultimately restoring type 1-mediated antitumor immunity, thereby securing a BrC-specific T cell response. These findings provide a clear rationale for clinical exploration of SLN-immune potentiation through local CpG/STAT3i administration in patients with BrC.

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Adorisio, Sabrina, Lorenza Cannarile, Domenico V. Delfino, and Emira Ayroldi. "Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?" Cells 10, no. 9 (September 6, 2021): 2333. http://dx.doi.org/10.3390/cells10092333.

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Programmed cell death protein 1 (PD-1) and its ligands, PD-L1/2, control T cell activation and tolerance. While PD-1 expression is induced upon T cell receptor (TCR) activation or cytokine signaling, PD-L1 is expressed on B cells, antigen presenting cells, and on non-immune tissues, including cancer cells. Importantly, PD-L1 binding inhibits T cell activation. Therefore, the modulation of PD-1/PD-L1 expression on immune cells, both circulating or in a tumor microenvironment and/or on the tumor cell surface, is one mechanism of cancer immune evasion. Therapies that target PD-1/PD-L1, blocking the T cell-cancer cell interaction, have been successful in patients with various types of cancer. Glucocorticoids (GCs) are often administered to manage the side effects of chemo- or immuno-therapy, exerting a wide range of immunosuppressive and anti-inflammatory effects. However, GCs may also have tumor-promoting effects, interfering with therapy. In this review, we examine GC signaling and how it intersects with PD-1/PD-L1 pathways, including a discussion on the potential for GC- and PD-1/PD-L1-targeted therapies to “confuse” the immune system, leading to a cancer cell advantage that counteracts anti-cancer immunotherapy. Therefore, combination therapies should be utilized with an awareness of the potential for opposing effects on the immune system.

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Ramoner, Reinhold, Thomas Putz, Hubert Gander, Andrea Rahm, Georg Bartsch, Claudia Schaber, and Martin Thurnher. "Dendritic-cell activation by secretory phospholipase A2." Blood 105, no. 9 (May 1, 2005): 3583–87. http://dx.doi.org/10.1182/blood-2004-08-3001.

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Abstract Dendritic cells (DCs), also referred to as the sentinels of the immune system, induce and coordinate important functions of immune surveillance. DCs acquire immunity-initiating capacity only after a process of maturation usually induced by ligands that bind to members of the tumor necrosis factor (TNF) or toll-like receptor families. Secretory phospholipase A2 (sPLA2), which hydrolyzes the sn-2 ester bond of glycerophospholipids, regulates a variety of cellular functions including migration of endothelial cells and neurite outgrowth. In the present study we investigated the role of sPLA2 in DC biology. We report that human monocyte-derived DC cultures lack sPLA2 activity but respond to exogenous sPLA2. sPLA2 alone and in cooperation with TNF-α and interleukin 1 β (IL-1β) induced fatty acid release from DC membranes, which was accompanied by upregulation of surface markers and by an increase in the migratory and immunostimulatory capacity of the DCs. Our findings indicate that secreted enzymes such as sPLA2 can contribute to DC maturation and emphasize the role of lipid mediators in the regulation of immune responses. This observation may also have implications for DC-based vaccine development.

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Kroesen, Bart-Jan, Pamela M. J. McLaughlin, Petra H. L. Schuilenga-Hut, Susan C. Jacobs, Grietje Molema, Wijnand Helfrich, and Lou F. M. H. De Leij. "Tumor-targeted immune complex formation: Effects on myeloid cell activation and tumor-directed immune cell migration." International Journal of Cancer 98, no. 6 (March 29, 2002): 857–63. http://dx.doi.org/10.1002/ijc.10245.

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Meier, Angela, Galit Alter, Nicole Frahm, Harlyn Sidhu, Bin Li, Aranya Bagchi, Nickolas Teigen, et al. "MyD88-Dependent Immune Activation Mediated by Human Immunodeficiency Virus Type 1-Encoded Toll-Like Receptor Ligands." Journal of Virology 81, no. 15 (May 16, 2007): 8180–91. http://dx.doi.org/10.1128/jvi.00421-07.

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ABSTRACT Immune activation is a major characteristic of human immunodeficiency virus type 1 (HIV-1) infection and a strong prognostic factor for HIV-1 disease progression. The underlying mechanisms leading to immune activation in viremic HIV-1 infection, however, are not fully understood. Here we show that, following the initiation of highly active antiretroviral therapy, the immediate decline of immune activation is closely associated with the reduction of HIV-1 viremia, which suggests a direct contribution of HIV-1 itself to immune activation. To propose a mechanism, we demonstrate that the single-stranded RNA of HIV-1 encodes multiple uridine-rich Toll-like receptor 7/8 (TLR7/8) ligands that induce strong MyD88-dependent plasmacytoid dendritic cell and monocyte activation, as well as accessory cell-dependent T-cell activation. HIV-1-encoded TLR ligands may, therefore, directly contribute to the immune activation observed during viremic HIV-1 infection. These data provide an initial rationale for inhibiting the TLR pathway to directly reduce the chronic immune activation induced by HIV-1 and the associated immune pathogenesis.

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Riegel, Kristina, Janine Schlöder, Marco Sobczak, Helmut Jonuleit, Bernd Thiede, Hansjörg Schild, and Krishnaraj Rajalingam. "RAF kinases are stabilized and required for dendritic cell differentiation and function." Cell Death & Differentiation 27, no. 4 (September 20, 2019): 1300–1315. http://dx.doi.org/10.1038/s41418-019-0416-4.

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Abstract RAF kinases (ARAF, BRAF, and CRAF) are highly conserved enzymes that trigger the RAF-MEK1/2-ERK1/2 (MAPK) pathway upon activation of RAS. Despite enormous clinical interest, relatively little is known on the role of RAFs in mediating immune responses. Here, we investigated the role of RAF kinases and MEK1/2 in dendritic cells (DCs), the central regulators of T cell-mediated antitumor immune responses and the adaptive immune system. We demonstrate that RAF kinases are active and stabilized at their protein levels during DC differentiation. Inhibition of RAF kinases but not MEK1/2 impaired the activation of DCs in both mice and human. As expected, DCs treated with RAF inhibitors show defects in activating T cells. Further, RAF and MEK1/2 kinases are directly required for the activation and proliferation of CD4+ T cells. Our observations suggest that RAF and MEK1/2 have independent roles in regulating DC function that has important implications for administering RAF–MAPK inhibitors in the clinics.

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