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Journal articles on the topic 'T-cell activation antigens'
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1
Williams, John M., Vicki E. Kelley, Robert L. Kirkman, Nicholas L. Tilney, Michael E. Shapiro, John R. Murphy, and Terry B. Strom. "T Cell Activation Antigens: Therapeutic Implications." Immunological Investigations 16, no. 8 (January 1987): 687–723. http://dx.doi.org/10.3109/08820138709087109.
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Moody, D. B. "T Cell Activation by Lipopeptide Antigens." Science 303, no. 5657 (January 23, 2004): 527–31. http://dx.doi.org/10.1126/science.1089353.
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Rhijn, Ildiko Van, Dirk M. Zajonc, Ian A. Wilson, and D. Branch Moody. "T-cell activation by lipopeptide antigens." Current Opinion in Immunology 17, no. 3 (June 2005): 222–29. http://dx.doi.org/10.1016/j.coi.2005.04.006.
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Dallman, M. J. "Antibodies to T cell activation antigens." Immunology Letters 29, no. 1-2 (July 1991): 173. http://dx.doi.org/10.1016/0165-2478(91)90225-y.
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Qin, Yingyu, Sejin Oh, Sojung Lim, Jung Hoon Shin, Min Sang Yoon, and Se-Ho Park. "Invariant NKT cells facilitate cytotoxic T-cell activation via direct recognition of CD1d on T cells." Experimental & Molecular Medicine 51, no. 10 (October 2019): 1–9. http://dx.doi.org/10.1038/s12276-019-0329-9.
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Abstract Invariant natural killer T (iNKT) cells are a major subset of NKT cells that recognize foreign and endogenous lipid antigens presented by CD1d. Although iNKT cells are characteristically autoreactive to self-antigens, the role of iNKT cells in the regulation of cytotoxic T lymphocytes (CTL) has been elucidated using α-galactosylceramide (α-GalCer), a strong synthetic glycolipid that is presented by professional antigen presenting cells (APCs), such as dendritic cells. Despite the well-known effects of α-GalCer and dendritic cells on lipid antigen presentation, the physiological role of endogenous antigens presented by CTLs during crosstalk with iNKT cells has not yet been addressed. In this study, we found that antigen-primed CTLs with transient CD1d upregulation could present lipid self-antigens to activate the iNKT cell production of IFN-γ. CTL-mediated iNKT cell activation in turn enhanced IFN-γ production and the proliferation and cytotoxicity of CTLs. We also found that the direct interaction of iNKT cells and CTLs enhanced the antitumor immune responses of CTLs. This partially explains the functional role of iNKT cells in CTL-mediated antitumor immunity. Our findings suggest that in the absence of exogenous iNKT cell ligands, iNKT cells enhanced the CTL production of IFN-γ and CTL proliferation and cytotoxicity via direct interaction with CD1d expressed on T cells without interacting with APCs.
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Welsh, Michael D., Hilary E. Kennedy, Allister J. Smyth, R. Martyn Girvin, Peter Andersen, and John M. Pollock. "Responses of Bovine WC1+ γδ T Cells to Protein and Nonprotein Antigens of Mycobacterium bovis." Infection and Immunity 70, no. 11 (November 2002): 6114–20. http://dx.doi.org/10.1128/iai.70.11.6114-6120.2002.
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ABSTRACT WC1+ γδ T cells of Mycobacterium bovis-infected cattle are highly responsive to M. bovis sonic extract (MBSE). In mycobacterial infections of other species, γδ T cells have been shown to respond to protein and nonprotein antigens, but the bovine WC1+ γδ T-cell antigenic targets within MBSE require further definition in terms of the dominance of protein versus nonprotein components. The present study sought to characterize the WC1+ γδ T-cell antigenic targets, together with the role of interleukin-2 (IL-2), in the context of M. bovis infection. This was achieved by testing crude and defined antigens to assess protein versus nonprotein recognition by WC1+ γδ T cells in comparison with CD4+ αβ T cells. Both cell types proliferated strongly in response to MBSE, with CD4+ T cells being the major producers of gamma interferon (IFN-γ). However, enzymatic digestion of the protein in MBSE removed its ability to stimulate CD4+ T-cell responses, whereas some WC1+ γδ T-cell proliferation remained. The most antigenic protein inducing proliferation and IFN-γ secretion in WC1+ γδ T-cell cultures was found to be ESAT-6, which is a potential novel diagnostic reagent and vaccine candidate. In addition, WC1+ γδ T-cell proliferation was observed in response to stimulation with prenyl pyrophosphate antigens (isopentenyl pyrophosphate and monomethyl phosphate). High levels of cellular activation (CD25 expression) resulted from MBSE stimulation of WC1+ γδ T cells from infected animals. A similar degree of activation was induced by IL-2 alone, but for WC1+ γδ T-cell division IL-2 was found to act only as a costimulatory signal, enhancing antigen-driven responses. Overall, the data indicate that protein antigens are important stimulators of WC1+ γδ T-cell proliferation and IFN-γ secretion in M. bovis infection, with nonprotein antigens inducing significant proliferation. These findings have important implications for diagnostic and vaccine development.
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Kambayashi, Taku, Jan D. Baranski, Rebecca G. Baker, Tao Zou, Eric J. Allenspach, Jonathan E. Shoag, Peter L. Jones, and Gary A. Koretzky. "Indirect involvement of allergen-captured mast cells in antigen presentation." Blood 111, no. 3 (February 1, 2008): 1489–96. http://dx.doi.org/10.1182/blood-2007-07-102111.
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Abstract It is generally thought that mast cells influence T-cell activation nonspecifically through the release of inflammatory mediators. In this report, we provide evidence that mast cells may also affect antigen-specific T-cell responses by internalizing immunoglobulin E–bound antigens for presentation to antigen-specific T cells. Surprisingly, T-cell activation did not require that mast cells express major histocompatibility complex class II, indicating that mast cells were not involved in the direct presentation of the internalized antigens. Rather, the antigen captured by mast cells is presented by other major histocompatibility complex class II+ antigen-presenting cells. To explore how this may occur, we investigated the fate of mast cells stimulated by antigen and found that FcϵRI crosslinking enhances mast cell apoptosis. Cell death by antigen-captured mast cells was required for efficient presentation because protection of mast cell death significantly decreased T-cell activation. These results suggest that mast cells may be involved in antigen presentation by acting as an antigen reservoir after antigen capture through specific immunoglobulin E molecules bound to their FcϵRI. This mechanism may contribute to how mast cells impact the development of T-cell responses.
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Rock, K. L., E. T. Yeh, C. F. Gramm, S. I. Haber, H. Reiser, and B. Benacerraf. "TAP, a novel T cell-activating protein involved in the stimulation of MHC-restricted T lymphocytes." Journal of Experimental Medicine 163, no. 2 (February 1, 1986): 315–33. http://dx.doi.org/10.1084/jem.163.2.315.
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Five mAbs have been generated and used to characterize TAP (T cell activating protein) a novel, functional murine T cell membrane antigen. The TAP molecule is a 12-kD protein that is synthesized by T cells. By antibody crossblocking, it appears to be closely associated with a 16-kD protein on the T cell membrane also identified with a novel mAb. These molecules are clearly distinct from the major well-characterized murine T cell antigens previously described. Antibody binding to TAP can result in the activation of MHC-restricted, antigen-specific inducer T cell hybridomas that is equivalent in magnitude to maximal antigen or lectin stimulation. This is a direct effect of soluble antibody and does not require accessory cells or other factors. The activating anti-TAP mAbs are also mitogenic for normal heterogeneous T lymphocytes in the presence of accessory cells or IL-1. In addition, these antibodies are observed to modulate specific immune stimulation. Thus, the activating anti-TAP mAbs synergise with antigen-specific stimulation of T cells, while a nonactivating anti-TAP mAb inhibits antigen driven activation. These observations suggest that the TAP molecule may participate in physiologic T cell activation. The possible relationship of TAP to known physiologic triggering structures, the T3-T cell receptor complex, is considered. TAP is expressed on 70% of peripheral T cells and therefore defines a major T cell subset, making it perhaps the first example of a murine subset-specific activating protein.
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McCloskey, Megan L., Maria A. Curotto de Lafaille, Michael C. Carroll, and Adrian Erlebacher. "Acquisition and presentation of follicular dendritic cell–bound antigen by lymph node–resident dendritic cells." Journal of Experimental Medicine 208, no. 1 (December 20, 2010): 135–48. http://dx.doi.org/10.1084/jem.20100354.
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Follicular dendritic cells (DCs [FDCs]) are prominent stromal cell constituents of B cell follicles with the remarkable ability to retain complement-fixed antigens on their cell surface for extended periods of time. These retained immune complexes have long been known to provide the antigenic stimulus that drives antibody affinity maturation, but their role in cellular immunity has remained unclear. In this study, we show that FDC-retained antigens are continually sampled by lymph node–resident DCs for presentation to CD8 T cells. This novel pathway of antigen acquisition was detectable when FDCs were loaded with purified antigens bound into classical antigen–antibody immune complexes, as well as after pregnancy, when they are loaded physiologically with antigens associated with the complement-fixed microparticles released from the placenta into maternal blood. In both cases, ensuing antigen presentation was profoundly tolerogenic, as it induced T cell deletion even under inflammatory conditions. These results significantly broaden the scope of FDC function and suggest new ways that the complement system and persistent antigen presentation might influence T cell activation and the maintenance of peripheral immune tolerance.
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Moris, Arnaud, Anthony Pajot, Fabien Blanchet, Florence Guivel-Benhassine, Margarita Salcedo, and Olivier Schwartz. "Dendritic cells and HIV-specific CD4+ T cells: HIV antigen presentation, T-cell activation, and viral transfer." Blood 108, no. 5 (September 1, 2006): 1643–51. http://dx.doi.org/10.1182/blood-2006-02-006361.
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Human immunodeficiency virus (HIV)-specific CD4+ lymphocytes are preferentially infected in HIV-positive individuals. To study this preferential infection, we have derived several HIV-specific (HS) CD4+ clones. We show that in dendritic cells (DCs), HIV virion capture led to major histocompatibility complex class-II (MHC-II)-restricted viral antigen presentation and to activation of HS cells. In contrast, neither cell-free virions nor infected lymphocytes activated HS cells. In DCs, the dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN/CD209), which internalizes virions, promoted MHC-II presentation of HIV antigens. Activation of HS cells by HIV-exposed DCs triggered an efficient viral spread in lymphocytes. CD4+ clones with irrelevant antigenic specificities were not activated by HIV-exposed DCs and poorly supported viral replication under this setting. Our results unravel the mechanisms of MHC-II-restricted HIV antigen presentation by DCs and describe how HIV gains access to the very cells designed by the immune system to counteract this pathogen.
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Haque, M. Azizul, Ping Li, Sheila K. Jackson, Hassane M. Zarour, John W. Hawes, Uyen T. Phan, Maja Maric, Peter Cresswell, and Janice S. Blum. "Absence of γ-Interferon–inducible Lysosomal Thiol Reductase in Melanomas Disrupts T Cell Recognition of Select Immunodominant Epitopes." Journal of Experimental Medicine 195, no. 10 (May 13, 2002): 1267–77. http://dx.doi.org/10.1084/jem.20011853.
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Long-lasting tumor immunity requires functional mobilization of CD8+ and CD4+ T lymphocytes. CD4+ T cell activation is enhanced by presentation of shed tumor antigens by professional antigen-presenting cells (APCs), coupled with display of similar antigenic epitopes by major histocompatibility complex class II on malignant cells. APCs readily processed and presented several self-antigens, yet T cell responses to these proteins were absent or reduced in the context of class II+ melanomas. T cell recognition of select exogenous and endogenous epitopes was dependent on tumor cell expression of γ-interferon–inducible lysosomal thiol reductase (GILT). The absence of GILT in melanomas altered antigen processing and the hierarchy of immunodominant epitope presentation. Mass spectral analysis also revealed GILT's ability to reduce cysteinylated epitopes. Such disparities in the profile of antigenic epitopes displayed by tumors and bystander APCs may contribute to tumor cell survival in the face of immunological defenses.
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Kanda, Yasuhiro, Taku Okazaki, and Tomoya Katakai. "Motility Dynamics of T Cells in Tumor-Draining Lymph Nodes: A Rational Indicator of Antitumor Response and Immune Checkpoint Blockade." Cancers 13, no. 18 (September 15, 2021): 4616. http://dx.doi.org/10.3390/cancers13184616.
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The migration status of T cells within the densely packed tissue environment of lymph nodes reflects the ongoing activation state of adaptive immune responses. Upon encountering antigen-presenting dendritic cells, actively migrating T cells that are specific to cognate antigens slow down and are eventually arrested on dendritic cells to form immunological synapses. This dynamic transition of T cell motility is a fundamental strategy for the efficient scanning of antigens, followed by obtaining the adequate activation signals. After receiving antigenic stimuli, T cells begin to proliferate, and the expression of immunoregulatory receptors (such as CTLA-4 and PD-1) is induced on their surface. Recent findings have revealed that these ‘immune checkpoint’ molecules control the activation as well as motility of T cells in various situations. Therefore, the outcome of tumor immunotherapy using checkpoint inhibitors is assumed to be closely related to the alteration of T cell motility, particularly in tumor-draining lymph nodes (TDLNs). In this review, we discuss the migration dynamics of T cells during their activation in TDLNs, and the roles of checkpoint molecules in T cell motility, to provide some insight into the effect of tumor immunotherapy via checkpoint blockade, in terms of T cell dynamics and the importance of TDLNs.
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Geiger, Rebekka, Thomas Duhen, Antonio Lanzavecchia, and Federica Sallusto. "Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells." Journal of Experimental Medicine 206, no. 7 (June 29, 2009): 1525–34. http://dx.doi.org/10.1084/jem.20090504.
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The enormous diversity of the naive T cell repertoire is instrumental in generating an immune response to virtually any foreign antigen that can be processed into peptides that bind to MHC molecules. The low frequency of antigen-specific naive T cells, their high activation threshold, and the constrains of antigen-processing and presentation have hampered analysis of naive repertoires to complex protein antigens. In this study, libraries of polyclonally expanded naive T cells were used to determine frequency and antigen dose–response of human naive CD4+ T cells specific for a variety of antigens and to isolate antigen-specific T cell clones. In the naive repertoire, T cells specific for primary antigens, such as KLH and Bacillus anthracis protective antigen, and for recall antigens, such as tetanus toxoid, cytomegalovirus, and Mycobacterium tuberculosis purified protein derivative, were detected at frequencies ranging from 5 to 170 cells per 106 naive T cells. Antigen concentrations required for half-maximal response (EC50) varied over several orders of magnitude for different naive T cells. In contrast, in the memory repertoire, T cells specific for primary antigens were not detected, whereas T cells specific for recall antigens were detected at high frequencies and displayed EC50 values in the low range of antigen concentrations. The method described may find applications for evaluation of vaccine candidates, for testing antigenicity of therapeutic proteins, drugs, and chemicals, and for generation of antigen-specific T cell clones for adoptive cellular immunotherapy.
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Gerner, Michael Y., Kerry A. Casey, Wolfgang Kastenmuller, and Ronald N. Germain. "Dendritic cell and antigen dispersal landscapes regulate T cell immunity." Journal of Experimental Medicine 214, no. 10 (August 28, 2017): 3105–22. http://dx.doi.org/10.1084/jem.20170335.
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Dendritic cell (DC) subsets with biased capacity for CD4+ and CD8+ T cell activation are asymmetrically distributed in lymph nodes (LNs), but how this affects adaptive responses has not been extensively studied. Here we used quantitative imaging to examine the relationships among antigen dispersal, DC positioning, and T cell activation after protein immunization. Antigens rapidly drained into LNs and formed gradients extending from the lymphatic sinuses, with reduced abundance in the deep LN paracortex. Differential localization of DCs specialized for major histocompatibility complex I (MHC I) and MHC II presentation resulted in preferential activation of CD8+ and CD4+ T cells within distinct LN regions. Because MHC I–specialized DCs are positioned in regions with limited antigen delivery, modest reductions in antigen dose led to a substantially greater decline in CD8+ compared with CD4+ T cell activation, expansion, and clonal diversity. Thus, the collective action of antigen dispersal and DC positioning regulates the extent and quality of T cell immunity, with important implications for vaccine design.
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Greenstein, J. L., B. Malissen, and S. J. Burakoff. "Role of L3T4 in antigen-driven activation of a class I-specific T cell hybridoma." Journal of Experimental Medicine 162, no. 1 (July 1, 1985): 369–74. http://dx.doi.org/10.1084/jem.162.1.369.
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The expression of L3T4/Lyt-2 on murine T cells has led to the association of these surface markers with recognition of either class II or class I major histo-compatibility complex (MHC) antigens. It has been suggested that these T cell surface antigens interact with nonpolymorphic determinants on MHC antigens. We have examined the role of L3T4 in the recognition of H-2Dd by the T cell hybridoma, 3DT52.5. Mouse L cells transfected with either the H-2Dd gene, or with both the alpha and beta genes of I-Ak and the H-2Dd gene have been used to assess the role of an L3T4/la interaction at varying doses of H-2Dd. A role of L3T4 in activation of 3DT52.5 becomes evident only at limiting doses of antigen. It appears that an L3T4/la interaction can influence T cell function during suboptimal stimulation, implying that the L3T4/la interaction serves to raise the functional affinity of interaction between the T cell and the antigen-bearing cell.
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Wang, Xiaohua, Xiuxu Chen, Lance Rodenkirch, William Simonson, Sarah Wernimont, Rachel M. Ndonye, Natacha Veerapen, et al. "Natural killer T-cell autoreactivity leads to a specialized activation state." Blood 112, no. 10 (November 15, 2008): 4128–38. http://dx.doi.org/10.1182/blood-2008-05-157529.
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Abstract Natural killer T (NKT) cells are innate-like T cells that recognize specific microbial antigens and also display autoreactivity to self-antigens. The nature of NKT-cell autoreactive activation remains poorly understood. We show here that the mitogen-activated protein kinase (MAPK) pathway is operative during human NKT-cell autoreactive activation, but calcium signaling is severely impaired. This results in a response that is biased toward granulocyte macrophage colony-stimulating factor (GM-CSF) secretion because this cytokine requires extracellular signal-regulated kinase (ERK) signaling but is not highly calcium dependent, whereas interferon-γ (IFN-γ), interleukin (IL)–4, and IL-2 production are minimal. Autoreactive activation was associated with reduced migration velocity but did not induce arrest; thus, NKT cells retained the ability to survey antigen presenting cells (APCs). IL-12 and IL-18 stimulated autoreactively activated NKT cells to secrete IFN-γ, and this was mediated by Janus kinase-signal transducers and activators of transcription (JAK-STAT)–dependent signaling without induction of calcium flux. This pathway did not require concurrent contact with CD1d+ APCs but was strictly dependent on preceding autoreactive stimulation that induced ERK activation. In contrast, NKT-cell responses to the glycolipid antigen α-galactosyl ceramide (α-GalCer) were dampened by prior autoreactive activation. These results show that NKT-cell autoreactivity induces restricted cytokine secretion and leads to altered basal activation that potentiates innate responsiveness to costimulatory cytokines while modulating sensitivity to foreign antigens.
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Busch, Elena, Kristina D. Kubon, Johanna K. M. Mayer, Gemma Pidelaserra-Martí, Jessica Albert, Birgit Hoyler, Johannes P. W. Heidbuechel, et al. "Measles Vaccines Designed for Enhanced CD8+ T Cell Activation." Viruses 12, no. 2 (February 21, 2020): 242. http://dx.doi.org/10.3390/v12020242.
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Priming and activation of CD8+ T cell responses is crucial to achieve anti-viral and anti-tumor immunity. Live attenuated measles vaccine strains have been used successfully for immunization for decades and are currently investigated in trials of oncolytic virotherapy. The available reverse genetics systems allow for insertion of additional genes, including heterologous antigens. Here, we designed recombinant measles vaccine vectors for priming and activation of antigen-specific CD8+ T cells. For proof-of-concept, we used cytotoxic T lymphocyte (CTL) lines specific for the melanoma-associated differentiation antigen tyrosinase-related protein-2 (TRP-2), or the model antigen chicken ovalbumin (OVA), respectively. We generated recombinant measles vaccine vectors with TRP-2 and OVA epitope cassette variants for expression of the full-length antigen or the respective immunodominant CD8+ epitope, with additional variants mediating secretion or proteasomal degradation of the epitope. We show that these recombinant measles virus vectors mediate varying levels of MHC class I (MHC-I)-restricted epitope presentation, leading to activation of cognate CTLs, as indicated by secretion of interferon-gamma (IFNγ) in vitro. Importantly, the recombinant OVA vaccines also mediate priming of naïve OT-I CD8+ T cells by dendritic cells. While all vaccine variants can prime and activate cognate T cells, IFNγ release was enhanced using a secreted epitope variant and a variant with epitope strings targeted to the proteasome. The principles presented in this study will facilitate the design of recombinant vaccines to elicit CD8+ responses against pathogens and tumor antigens.
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Ho, W. Y., M. P. Cooke, C. C. Goodnow, and M. M. Davis. "Resting and anergic B cells are defective in CD28-dependent costimulation of naive CD4+ T cells." Journal of Experimental Medicine 179, no. 5 (May 1, 1994): 1539–49. http://dx.doi.org/10.1084/jem.179.5.1539.
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Successful antibody production in vivo depends on a number of cellular events, one of the most important of these being cognate B cell-T cell interaction. To examine this phenomenon in vitro, homogeneous populations of hen egg lysozyme (HEL)-specific small resting B cells and naive CD4+ HEL-specific T cells (derived from immunoglobulin [Ig] and T cell receptor transgenic mice, respectively) were cultured together. On addition of intact HEL protein. HEL-specific B cells increase their expression of activation molecules, including a B7-related protein and CD44, and enlarge into blast cells. Within the same cultures, HEL-specific CD4+ T cells also increase expression of the activation markers CD69 and CD44, enlarge, secrete lymphokines, and proliferate. This response is radiation sensitive, supporting the conclusion that HEL-specific B cells present antigen to and activate the naive T cells. By contrast, when a synthetic peptide fragment of HEL is used to bypass B cell antigen-receptor engagement, the naive T cells enlarge and display activation antigens, but fail to produce lymphokines, proliferate, or promote B cell blastogenesis. Presentation of HEL by tolerant B cells, which are no longer able to signal effectively through their antigen receptors, results in an identical pattern of incomplete T cell activation. Addition of a stimulating anti-CD28 antibody and blocking of CD28 signals with CTLA4/Ig fusion protein both show that complete activation of naive CD4+ T cells depends on the initial induction of B7 and related costimulatory molecules after HEL binding to nontolerant HEL-specific B cells. Thus, in the absence of adequate constimulation from the B cell, naive CD4+ T cells undergo a form of "partial activation" in which they upregulate surface expression of certain T cell activation antigens, but fail to efficiently produce lymphokine and proliferate. This may explain the different conclusions that have been reached regarding the consequences of B cell antigen presentation to T cells, in that the ability of B cells to activate naive CD4+ T cells depends both on their specificity and their activation state.
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Davies, T. F., S. H. Roman, W. A. Mackenzie, N. Goldsmith, S. M. Dower, and L. A. Piccinini. "Thyroid cell MHC class II antigens:." Acta Endocrinologica 116, no. 1_Suppl (August 1987): S13—S20. http://dx.doi.org/10.1530/acta.0.114s013.
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Abstract. An association exists between certain MHC polymorphisms and autoimmune thyroid disease in animals and humans. The observation of MHC class II antigen expression by the thyroid suggests that such associations may have mechanistic explanations at the level of the thyroid cell. Such class II antigen expression, rather than being a constitutive property of thyroid epithelium, appears to be primarily mediated by lymphokine secretion from intrathyroidal T lymphocytes and a variety of agents, for example TSH and TSH receptor antibodies, may amplify such lymphokine action. Thyroid cell class II antigens participate in activation and amplification of T cells and are involved in presentation of thyroid antigen to the immune system. The relationship between these local immune interactions and the initial events leading to the development of autoimmune thyroid disease requires a more fundamental understanding of the workings of the immune system at the site of antigenic stimulation.
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Allan, Lenka L., Katrin Hoefl, Dong-Jun Zheng, Brian K. Chung, Frederick K. Kozak, Rusung Tan, and Peter van den Elzen. "Apolipoprotein-mediated lipid antigen presentation in B cells provides a pathway for innate help by NKT cells." Blood 114, no. 12 (September 17, 2009): 2411–16. http://dx.doi.org/10.1182/blood-2009-04-211417.
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Abstract Natural killer T (NKT) cells are innate-like lymphocytes that recognize lipid antigens and have been shown to enhance B-cell activation and antibody production. B cells typically recruit T-cell help by presenting internalized antigens recognized by their surface antigen receptor. Here, we demonstrate a highly efficient means whereby human B cells present lipid antigens to NKT cells, capturing the antigen using apolipoprotein E (apoE) and the low-density lipoprotein receptor (LDL-R). ApoE dramatically enhances B-cell presentation of alpha-galactosylceramide (αGalCer), an exogenous CD1d presented antigen, inducing activation of NKT cells and the subsequent activation of B cells. B cells express the LDL-R on activation, and the activation of NKT cells by B cells is completely LDL-R dependent, as shown by blocking experiments and the complete lack of presentation when using apoE2, an isoform of apoE incapable of LDL-R binding. The dependence on apoE and the LDL-R is much more pronounced in B cells than we had previously seen in dendritic cells, which can apparently use alternate pathways of lipid antigen uptake. Thus, B cells use an apolipoprotein-mediated pathway of lipid antigen presentation, which constitutes a form of innate help for B cells by NKT cells.
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Bernhardt, Anna Luise, Sascha Kretschmann, Judith Bausenwein, Heidi Balzer, Andreas Mackensen, and Anita Natalie Kremer. "Characterizing the Immunogenicity of DM-Sensitive and DM-Resistant Antigens." Blood 132, Supplement 1 (November 29, 2018): 3310. http://dx.doi.org/10.1182/blood-2018-99-112103.
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Abstract Introduction: The separation of graft-versus-leukemia (GvL) effect from graft-versus-host-disease (GvHD) is a major objective after allogeneic stem cell transplantation. We recently described two types of endogenous HLA class II restricted antigens depending on their behavior towards HLA-DM. While DM-resistant antigens are presented in the presence of HLA-DM, presentation of DM-sensitive antigens rely on co-expression of HLA-DO - the natural inhibitor of HLA-DM. Since the expression of HLA-DO is not upregulated by inflammatory cytokines and restricted to B-cells, dendritic cells and thymic epithelial cells, DM-sensitive antigens cannot be presented on non-hematopoietic tissues. Therefore, usage of CD4 T-cells directed against DM-sensitive antigens might allow separation of GvL from GvHD. However, it remains elusive whether immunogenicity and anti-tumorigenic potential of DM-sensitive and DM-resistant antigens have comparable properties in vivo. Methods: Therefore, we sought to create an in vivo system using a DM-sensitive and a DM-resistant variant of the same model antigen. First, we generated murine cell lines overexpressing either H2-M or H2-O (murine HLA-DM or HLA-DO, respectively) to allocate the two model antigens ovalbumin (OVA) and murine Y-chromosome antigen DBY to their category. Furthermore, we introduced one to three amino acid substitutions within the MHC II restricted T-cell epitopes of the two antigens and tested DM-sensitivity or DM-resistance by T-cell activation using proliferation and IFN-g secretion as read-out in vitro. Finally, we vaccinated B6 mice with the generated epitope variants and measured expansion, phenotype and reactivity of OVA- or DBY-specific CD4 T-cells in vivo. Results: By testing T-cell recognition of OVA or DBY on murine B-cell lines overexpressing H2-M and H2-O, respectively, we could show that OVA leads to a more potent T-cell activation in the presence of H2-O demonstrating its DM-sensitive character. In contrast the wildtype epitope of DBY does not rely on H2-O expression for strong T-cell activation and was therefore assessed as DM-resistant antigen. By introducing one to three amino acid substitutions within the T-cell epitope we could generate one further DM-sensitive variant of OVA but also two DM-resistant counterparts. Likewise, we designed both DM-resistant and DM-sensitive epitope variants of murine DBY. To assess T-cell receptor avidity to our epitope variants presented on natural antigen presenting cells, titration of DM-sensitive and DM-resistant variants of the same antigen on untreated splenocytes from OVA or DBY T-cell receptor transgenic mice, respectively, were performed. We observed comparable activation of the same T-cell clone activated by either variant of the epitope as measured by proliferation and IFN-g secretion. Furthermore, upon vaccination of B6 mice with either variant of the epitope we could measure comparable expansion, phenotype, and reactivity of OVA- and DBY-specific T-cells both invivo and ex vivo. Conclusion: We successfully generated DM-sensitive and DM-resistant variants of the same epitope for the two model antigens OVA and murine DBY. With this tool we could demonstrate that DM-sensitive antigens are not inferior to their DM-resistant counterpart. Therefore, targeting DM-sensitive antigens after allogenic stem cell transplantation might be an interesting tool to improve the GvL effect with only limited GvHD. Disclosures Bernhardt: DFG TRR221/project A1 (German Research Foundation): Research Funding.
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Pischel, K. D., H. G. Bluestein, and V. L. Woods. "Very late activation antigens (VLA) are human leukocyte-neuronal crossreactive cell surface antigens." Journal of Experimental Medicine 164, no. 2 (August 1, 1986): 393–406. http://dx.doi.org/10.1084/jem.164.2.393.
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The antigenic relationship between human neuronal and lymphocyte cell surface antigens has been analyzed using heteroantisera raised against human peripheral blood mononuclear cells (PBMC). The specificities of the crossreactive antigens were examined by immunoprecipitation of 125I-labeled SK-N-SH cultured neuronal cells using rabbit anti-PBMC (RAPBMC) sera and compared to known specificities using mAb. The predominant reactivity of each rabbit antiserum tested against SK-N-SH cells was with three molecules of 130,000, 160,000, and 180,000 Mr. These three chains comigrated with three molecules precipitated with the very late activation antigen (VLA)-specific mAb A-1A5. Sequential precipitations with mAb A-1A5 established that the three RAPBMC-precipitated bands were members of the VLA complex. This was confirmed by two-dimensional PAGE of the RAPBMC and A-1A5 immunoprecipitates, which were indistinguishable from one another. The two-dimensional pattern was more complex than was anticipated from the heterodimeric model of VLA chain association, and suggests an additional 130,000 Mr component of VLA. The three chains of the VLA complex precipitated by RAPBMC or mAb A-1A5 from SK-N-SH neurons closely resembled the VLA pattern present on activated T cells, including the 180,000 Mr activation-specific alpha 1 chain recognized by mAb TS2/7. Normal brain cell membranes also contain VLA molecules that are precipitated by RAPBMC and mAb A-1A5. Thus the VLA complex provides potentially important shared immunogens on human neurons and T cells.
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Huntimer, Lucas M., Kathleen A. Ross, Ross J. Darling, Nicole E. Winterwood, Paola Boggiatto, Balaji Narasimhan, Amanda E. Ramer-Tait, and Michael J. Wannemuehler. "Polyanhydride nanovaccine platform enhances antigen-specific cytotoxic T cell responses." TECHNOLOGY 02, no. 02 (June 2014): 171–75. http://dx.doi.org/10.1142/s2339547814500162.
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Polyanhydride nanoparticle-based vaccines (or nanovaccines) stabilize protein antigens, provide sustained antigen release leading to prolonged antigen presence, enhance activation of antigen presenting cells, and elicit protective immunity against respiratory infections upon challenge. However, induction of cell-mediated immunity when mice are immunized with polyanhydride nanovaccines has not been evaluated. Using a transgenic ovalbumin-specific T cell adoptive transfer model, we report the induction of antigen-specific cytotoxic CD8+ T cells expressing an effector memory phenotype by seven days after immunization with nanovaccine formulations. Furthermore, mice immunized with polyanhydride nanovaccines demonstrated enhanced recall responses after antigen re-exposure 35 days post-immunization indicating the activation and recruitment of antigen-specific memory CD8+ T cells to the site of antigen deposition.
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Ritvo, Paul-Gydeon, Ahmed Saadawi, Pierre Barennes, Valentin Quiniou, Wahiba Chaara, Karim El Soufi, Benjamin Bonnet, et al. "High-resolution repertoire analysis reveals a major bystander activation of Tfh and Tfr cells." Proceedings of the National Academy of Sciences 115, no. 38 (August 29, 2018): 9604–9. http://dx.doi.org/10.1073/pnas.1808594115.
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T follicular helper (Tfh) and regulatory (Tfr) cells are terminally differentiated cells found in germinal centers (GCs), specialized secondary lymphoid organ structures dedicated to antibody production. As such, follicular T (Tfol) cells are supposed to be specific for immunizing antigens, which has been reported for Tfh cells but is debated for Tfr cells. Here, we used high-throughput T cell receptor (TCR) sequencing to analyze the repertoires of Tfh and Tfr cells, at homeostasis and after immunization with self- or foreign antigens. We observed that, whatever the conditions, Tfh and Tfr cell repertoires are less diverse than those of effector T cells and Treg cells of the same tissues; surprisingly, these repertoires still represent thousands of different sequences, even after immunization with a single antigen that induces a 10-fold increase in Tfol cell numbers. Thorough analysis of the sharing and network of TCR sequences revealed that a specific response to the immunizing antigen can only, but hardly, be detected in Tfh cells immunized with a foreign antigen and Tfr cells immunized with a self-antigen. These antigen-specific responses are obscured by a global stimulation of Tfh and Tfr cells that appears to be antigen-independent. Altogether, our results suggest a major bystander Tfol cell activation during the immune response in the GCs.
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Ngwenyama, Njabulo, Annet Kirabo, Mark Aronovitz, Francisco Velázquez, Francisco Carrillo-Salinas, Ane M. Salvador, Tania Nevers, et al. "Isolevuglandin-Modified Cardiac Proteins Drive CD4+ T-Cell Activation in the Heart and Promote Cardiac Dysfunction." Circulation 143, no. 12 (March 23, 2021): 1242–55. http://dx.doi.org/10.1161/circulationaha.120.051889.
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Background: Despite the well-established association between T-cell–mediated inflammation and nonischemic heart failure, the specific mechanisms triggering T-cell activation during the progression of heart failure and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)–modified proteins that function as cardiac neoantigens to elicit CD4+ T-cell receptor (TCR) activation and promote heart failure. Methods: We used transverse aortic constriction in mice to trigger myocardial oxidative stress and T-cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77 GFP reporter mice, which transiently express GFP on TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation–deficient MhcII −/− mice and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species and IsoLGs in eliciting T-cell immune responses in vivo by treating mice with the antioxidant TEMPOL and the IsoLG scavenger 2-hydroxybenzylamine during transverse aortic constriction, and ex vivo in mechanistic studies of CD4+ T-cell proliferation in response to IsoLG-modified cardiac proteins. Results: We discovered that TCR antigen recognition increases in the left ventricle as cardiac dysfunction progresses and identified a limited repertoire of activated CD4+ T-cell clonotypes in the left ventricle. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction because MhcII −/− mice reconstituted with CD4+ T cells and OTII mice immunized with their cognate antigen were protected from transverse aortic constriction–induced cardiac dysfunction despite the presence of left ventricle–infiltrated CD4+ T cells. Scavenging IsoLGs with 2-hydroxybenzylamine reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in reactive oxygen species–dependent dendritic cell accumulation of IsoLG protein adducts, which induced robust CD4+ T-cell proliferation. Conclusions: Our study demonstrates an important role of reactive oxygen species–induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T-cell activation within the heart.
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Horna, Pedro, Alex Cuenca, Fengdong Cheng, Jason Brayer, Hong-Wei Wang, Ivan Borrello, Hyam Levitsky, and Eduardo M. Sotomayor. "In vivo disruption of tolerogenic cross-presentation mechanisms uncovers an effective T-cell activation by B-cell lymphomas leading to antitumor immunity." Blood 107, no. 7 (April 1, 2006): 2871–78. http://dx.doi.org/10.1182/blood-2005-07-3014.
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AbstractBone marrow-derived antigen-presenting cells (APCs) play a central role in the induction of tolerance to tumor antigens expressed by B-cell lymphomas. Here we show that in vivo disruption of this APC-mediated tolerogenic mechanism unveils an intrinsic ability of malignant B cells to efficiently present tumor antigens to antigen-specific CD4+ T cells, resulting in a strong antitumor effect. This intrinsic antigen-presenting ability of malignant B cells is, however, overridden by tolerogenic bone marrow-derived APCs, leading instead to T-cell unresponsiveness and lack of antitumor effect. These results highlight the concept that therapeutic strategies aimed at enhancing the antigen-presenting function of B-cell lymphomas might not succeed unless the tolerogenic mechanisms mediated by bone marrow-derived APCs are disrupted in the first place.
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Brigl, Manfred, Raju V. V. Tatituri, Gerald F. M. Watts, Veemal Bhowruth, Elizabeth A. Leadbetter, Nathaniel Barton, Nadia R. Cohen, Fong-Fu Hsu, Gurdyal S. Besra, and Michael B. Brenner. "Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection." Journal of Experimental Medicine 208, no. 6 (May 9, 2011): 1163–77. http://dx.doi.org/10.1084/jem.20102555.
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Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological α-galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection. However, when we compared the role of microbial antigens versus innate cytokine-driven mechanisms, we found that iNKT cell interferon-γ production after in vitro stimulation or infection with diverse bacteria overwhelmingly depended on toll-like receptor–driven IL-12. Importantly, activation of iNKT cells in vivo during infection with Sphingomonas yanoikuyae or Streptococcus pneumoniae, pathogens which are known to express iNKT cell antigens and which require iNKT cells for effective protection, also predominantly depended on IL-12. Constitutive expression of high levels of IL-12 receptor by iNKT cells enabled instant IL-12–induced STAT4 activation, demonstrating that among T cells, iNKT cells are uniquely equipped for immediate, cytokine-driven activation. These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections.
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Wallet, Mark A., Pradip Sen, Rafael R. Flores, Yaming Wang, Zuoan Yi, Yingsu Huang, Clayton E. Mathews, et al. "MerTK is required for apoptotic cell–induced T cell tolerance." Journal of Experimental Medicine 205, no. 1 (January 14, 2008): 219–32. http://dx.doi.org/10.1084/jem.20062293.
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Self-antigens expressed by apoptotic cells (ACs) may become targets for autoimmunity. Tolerance to these antigens is partly established by an ill-defined capacity of ACs to inhibit antigen-presenting cells such as dendritic cells (DCs). We present evidence that the receptor tyrosine kinase Mer (MerTK) has a key role in mediating AC-induced inhibition of DC activation/maturation. Pretreatment of DCs prepared from nonobese diabetic (NOD) mice with AC blocked secretion of proinflammatory cytokines, up-regulation of costimulatory molecule expression, and T cell activation. The effect of ACs on DCs was dependent on Gas6, which is a MerTK ligand. NOD DCs lacking MerTK expression (NOD.MerTKKD/KD) were resistant to AC-induced inhibition. Notably, autoimmune diabetes was exacerbated in NOD.MerTKKD/KD versus NOD mice expressing the transgenic BDC T cell receptor. In addition, β cell–specific CD4+ T cells adoptively transferred into NOD.MerTKKD/KD mice in which β cell apoptosis was induced with streptozotocin exhibited increased expansion and differentiation into type 1 T cell effectors. In both models, the lack of MerTK expression was associated with an increased frequency of activated pancreatic CD11c+CD8α+ DCs, which exhibited an enhanced T cell stimulatory capacity. These findings demonstrate that MerTK plays a critical role in regulating self-tolerance mediated between ACs, DCs, and T cells.
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Zhang, Di, Lihua Shi, Susan Tam, and Man-Cheong Fung. "Novel synthetic immune modulators for the activation of tumor antigen-specific T cells." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15203-e15203. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15203.
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e15203 Background: Although checkpoint inhibitor immunotherapy and adoptive T-cell therapy revolutionized cancer treatments, such approaches suffer either from lack of target specificity for checkpoint inhibitors or inability to target intracellular tumor-related antigens from CAR-T therapy. Here, we report the development of novel Tavo Immune Modulator (TIM) biologics molecules which can specifically recognize tumor antigen-specific T cells through an engineered pMHC complex with peptides derived from intracellular tumor-related antigens. These molecules can selectively activate such T cells through engineered T cell co-stimulatory modulators for enhanced tumor cell killing. Methods: NY-ESO-1 and MAGE-A10 TIM molecules were constructed as fusions of HLA-A*02:01 MHC complexed with either NY-ESO-1 (157-165) or MAGE-A10 (254-262) epitope peptides at the N-termini and various T cell costimulatory modulators at the C-termini of IgG heavy and light chains. TIM molecules were expressed in Expi293 cells and purified by Protein A affinity chromatography. Specific binding of TIM with cancer specific T cells was evaluated by immunostaining. The activation and proliferation of tumor specific CD8+ T cells were confirmed in T cell activation and recall assays. Results: Both NY-ESO-1 and MAGE-A10 specific TIM molecules were generated which recognized corresponding tumor specific T cells. NY-ESO-1 TIM engineered with IL2 could activate NY-ESO-1 specific CD8+ T cell exclusively. Engineering additional T cell costimulatory factors along with IL2 on NY-ESO-1 TIM molecule could further boost T cell proliferation and activation in T cell recall assays. Besides NY-ESO-1, combinations of T cell costimulatory factors with MAGE-A10 TIM molecules enhanced specific T cell activation. Additional in vitro and in vivo studies are ongoing to demonstrate efficacy of such novel TIM molecules in eliminating different types of NY-ESO-1 and MAGE-A10 which are over-expressed on tumor cells. Conclusions: This study demonstrates the utility of NY-ESO-1 and MAGE-A10 TIM molecules in the selective recognition and activation of tumor antigen-specific T cells. Such novel biologics molecules may provide target specificity in tumor treatment, and potential targeting of intracellular tumor-related antigens presented as peptides in MHC complexes on cell surfaces. Selective activation of tumor-specific T cells may provide a unique method for the treatment of various solid tumors and warrants further investigation.
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Bierer, B. E., A. Peterson, J. C. Gorga, S. H. Herrmann, and S. J. Burakoff. "Synergistic T cell activation via the physiological ligands for CD2 and the T cell receptor." Journal of Experimental Medicine 168, no. 3 (September 1, 1988): 1145–56. http://dx.doi.org/10.1084/jem.168.3.1145.
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T cells may be activated either by the antigen-specific T cell receptor (TCR)-CD3 complex or the cell surface receptor CD2. A natural ligand for CD2 has been found to be lymphocyte function-associated antigen 3 (LFA-3), a widely distributed cell surface glycoprotein. To investigate the interaction of these two pathways, we have expressed the cDNA encoding the human CD2 molecule in a murine T cell hybridoma that produces IL-2 in response to HLA-DR antigens. Expression of the CD2 molecule markedly enhances IL-2 production in response to LFA-3+ antigen-bearing stimulator cells, and this stimulation is inhibited by anti-CD2 and anti-LFA-3 mAb. To further define the role of LFA-3 in antigen-dependent T cell activation, we have studied the ability of the purified ligands of CD2 and the TCR to stimulate the hybridoma. Neither liposomes containing purified HLA-DR antigens nor liposomes containing purified LFA-3 were able to stimulate the parent or the CD2+ hybridoma. However, liposomes containing both purified LFA-3 and HLA-DR, the physiological ligands for CD2 and the TCR, respectively, stimulate IL-2 production by the CD2+ but not the parent hybridoma, suggesting that complementary interactions between the TCR-CD3 complex and the CD2 pathway may regulate lymphocyte activation. To determine whether the CD2/LFA-3 interaction participates in cell-cell adhesion and provides an activation signal, we have constructed a cytoplasmic deletion mutant of CD2, CD2 delta B, in which the COOH-terminal 100 amino acids of CD2 have been replaced with a serine. Hybridomas expressing the CD2 delta B molecule were examined. Deletion of the cytoplasmic domain of CD2 did not alter binding of LFA-3 but eliminated the ability of CD2 to increase the response of the hybridoma to liposomes containing both HLA-DR and LFA-3, demonstrating that adhesion of LFA-3 to CD2 alone was insufficient for activation, and that the cytoplasmic domain was required for LFA-3 stimulation through the CD2 molecule. T cells may be activated by purified LFA-3 binding to CD2 and the TCR interacting with its ligand, and these signals appear to be synergistic for the T cell. These results suggest that the CD2/LFA-3 interaction not only plays a role in cell-cell adhesion but provides a stimulatory signal for T cell activation.
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Sarobe, Pablo, Juan José Lasarte, Noelia Casares, Ascensión López-Díaz de Cerio, Elena Baixeras, Pablo Labarga, Nicolás García, Francisco Borrás-Cuesta, and Jesús Prieto. "Abnormal Priming of CD4+ T Cells by Dendritic Cells Expressing Hepatitis C Virus Core and E1 Proteins." Journal of Virology 76, no. 10 (May 15, 2002): 5062–70. http://dx.doi.org/10.1128/jvi.76.10.5062-5070.2002.
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ABSTRACT Patients infected with hepatitis C virus (HCV) have an impaired response against HCV antigens while keeping immune competence for other antigens. We hypothesized that expression of HCV proteins in infected dendritic cells (DC) might impair their antigen-presenting function, leading to a defective anti-HCV T-cell immunity. To test this hypothesis, DC from normal donors were transduced with an adenovirus coding for HCV core and E1 proteins and these cells (DC-CE1) were used to stimulate T lymphocytes. DC-CE1 were poor stimulators of allogeneic reactions and of autologous primary and secondary proliferative responses. Autologous T cells stimulated with DC-CE1 exhibited a pattern of incomplete activation characterized by enhanced CD25 expression but reduced interleukin 2 production. The same pattern of incomplete lymphocyte activation was observed in CD4+ T cells responding to HCV core in patients with chronic HCV infection. However, CD4+ response to HCV core was normal in patients who cleared HCV after alpha interferon therapy. Moreover, a normal CD4+ response to tetanus toxoid was found in both chronic HCV carriers and patients who had eliminated the infection. Our results suggest that expression of HCV structural antigens in infected DC disturbs their antigen-presenting function, leading to incomplete activation of anti-HCV-specific T cells and chronicity of infection. However, presentation of unrelated antigens by noninfected DC would allow normal T-cell immunity to other pathogens.
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Benmebarek, M., BL Cadilha, M. Hermann, S. Lesch, C. Augsburger, B. Brauchle, S. Stoiber, et al. "L4 Synthetic agonistic receptor-activating BiTEs – a modular platform for the efficient targeting of acute myeloid leukemia." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A2.2—A3. http://dx.doi.org/10.1136/jitc-2020-itoc7.4.
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BackgroundTargeted immunotherapies have shown limited success in the context of acute myeloid leukemia (AML). Due to the mutational landscape and heterogeneity attributed to this malignancy and toxicities associated with the targeting of myeloid lineage antigens, it has become apparent that a modular and controllable cell therapy approach with the potential to target multiple antigens is required. We propose a controlled ACT approach, where T cells are armed with synthetic agonistic receptors (SARs) that are conditionally activated only in the presence of a target AML-associated antigen, and a cross-linking bispecific T cell engager (BiTE) specific for both (SAR) T cell and tumour cell.Materials and MethodsA SAR composed of an extracellular EGFRvIII, trans-membrane CD28, and intracellular CD28 and CD3z domains was fused via overlap-extension PCR cloning. T cells were retrovirally transduced to stably express our SAR construct. SAR-specific bispecific T cell engagers (BiTE) that target AML-associated antigens were designed and expressed in Expi293FTMcells and purified by nickel affinity and size exclusion chromatography (SEC). We validated our approach in three human cancer models and patient-derived AML blasts expressing our AML-associated target antigen CD33.ResultsCD33-EGFRvIII BiTE, monovalently selective for our SAR, induced conditional antigen-dependent activation, proliferation and differentiation of SAR-T cells. Further, SAR T cells bridged to their target cells by BiTE could form functional immunological synapses, resulting in efficient tumor cell lysis with specificity towards CD33-expressing AML cells. SAR.BiTE combination could also mediate specific cytotoxicity against patient-derived AML blasts whilst driving SAR T cell activation. In vivo, treatment with SAR.BiTE combination could efficiently eradicate leukemia and enhance survival in an AML xenograft model. Furthermore, we could show selective activation of SAR T cells, as well as a controllable reversibility of said activation upon depletion of the T cell engaging molecule.ConclusionsHere we apply the SAR x BiAb approach in efforts to deliver specific and conditional activation of agonistic receptor-transduced T cells, and targeted tumour cell lysis. The modularity of our platform will allow for a multi-targeting ACT approach with the potential to translate the ACT successes of B cell malignancies to AML. With a lack of truly specific AML antigens, it is invaluable that this approach possesses an intrinsic safety switch via its BiTE facet. Moreover, we are able to circumvent pan-T cell activation due to the specific targeting and activation of SAR T cells.Disclosure InformationM. Benmebarek: None. B.L. Cadilha: None. M. Hermann: None. S. Lesch: None. C. Augsburger: None. B. Brauchle: None. S. Stoiber: None. A. Darwich: None. F. Rataj: None. C. Klein: A. Employment (full or part-time); Significant; Roche. K. Hopfner: None. M. Subklewe: None. S. Endres: None. S. Kobold: None.
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Zarozinski, Christopher C., James M. McNally, Barbara L. Lohman, Keith A. Daniels, and Raymond M. Welsh. "Bystander Sensitization to Activation-Induced Cell Death as a Mechanism of Virus-Induced Immune Suppression." Journal of Virology 74, no. 8 (April 15, 2000): 3650–58. http://dx.doi.org/10.1128/jvi.74.8.3650-3658.2000.
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ABSTRACT Viral infections which induce strong T-cell responses are often characterized by a period of transient immunodeficiency associated with the failure of host T cells to proliferate in response to mitogens or to mount memory recall responses to other antigens. During acute infections, most of the activated, proliferating virus-specific T cells are sensitized to undergo apoptosis on strong T-cell receptor (TCR) stimulation, but it has not been known why memory T cells not specific for the virus fail to proliferate on exposure to their cognate antigen. Using a lymphocytic choriomeningitis virus (LCMV) infection model in which LCMV-immune Thy 1.1+ splenocytes are adoptively transferred into Thy 1.2+ LCMV carrier mice, we demonstrate here that T cells clearly defined as not specific for the virus are sensitized to undergo activation-induced cell death on TCR stimulation in vitro. This bystander sensitization was in part dependent on the expression of Fas ligand (FasL) on the activated virus-specific cells and gamma interferon (IFN-γ) receptor expression on the bystander T cells. We propose that FasL from highly activated antiviral T cells may sensitize IFN-γ-conditioned T cells not specific for the virus to undergo apoptosis rather than to proliferate on encountering antigen. This may in part explain the failure of memory T cells to respond to recall antigens during acute and persistent viral infections.
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Kalergis, Alexis M., and Jeffrey V. Ravetch. "Inducing Tumor Immunity through the Selective Engagement of Activating Fcγ Receptors on Dendritic Cells." Journal of Experimental Medicine 195, no. 12 (June 17, 2002): 1653–59. http://dx.doi.org/10.1084/jem.20020338.
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Induction of tumor-specific immunity requires that dendritic cells (DCs) efficiently capture and present tumor antigens to result in the expansion and activation of tumor-specific cytotoxic T cells. The transition from antigen capture to T cell stimulation requires a maturation signal; in its absence tolerance, rather than immunity may develop. While immune complexes (ICs) are able to enhance antigen capture, they can be poor at inducing DC maturation, naive T cell activation and protective immunity. We now demonstrate that interfering with the inhibitory signal delivered by FcγRIIB on DCs converts ICs to potent maturation agents and results in T cell activation. Applying this approach to immunization with DCs pulsed ex-vivo with ICs, we have generated antigen-specific CD8+ T cells in vivo and achieved efficient protective immunity in a murine melanoma model. These data imply that ICs may normally function to maintain tolerance through the binding to inhibitory FcγRs on DCs, but they can be converted to potent immunogenic stimuli by selective engagement of activating FcγRs. This mechanism suggests a novel approach to the development of tumor vaccines.
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Klechevsky, Eynav, Anne-Laure Flamar, Yanying Cao, Jean-Philippe Blanck, Maochang Liu, Amy O'Bar, Olivier Agouna-Deciat, et al. "Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR." Blood 116, no. 10 (September 9, 2010): 1685–97. http://dx.doi.org/10.1182/blood-2010-01-264960.
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Abstract We evaluated human CD8+ T-cell responses generated by targeting antigens to dendritic cells (DCs) through various lectin receptors. We found the immunoreceptor tyrosine-based inhibitory motif-containing DC immunoreceptor (DCIR) to mediate potent cross-presentation. A single exposure to a low dose of anti-DCIR–antigen conjugate initiated antigen-specific CD8+ T-cell immunity by all human DC subsets including ex vivo–generated DCs, skin-isolated Langerhans cells, and blood myeloid DCs and plasmacytoid DCs. The delivery of influenza matrix protein (FluMP) through DCIR resulted in expansion of FluMP-specific memory CD8+ T cells. Enhanced specific CD8+ T-cell responses were observed when an antigen was delivered to the DCs via DCIR, compared with those induced by a free antigen, or antigen conjugated to a control monoclonal antibody or delivered via DC-SIGN, another lectin receptor. DCIR targeting also induced primary CD8+ T-cell responses against self (MART-1) and viral (HIV gag) antigens. Addition of Toll-like receptor (TLR) 7/8 agonist enhanced DCIR-mediated cross-presentation as well as cross-priming, particularly when combined with a CD40 signal. TLR7/8 activation was associated with increased expansion of the primed CD8+ T cells, high production of interferon-γ and tumor necrosis factor-α, and reduced levels of type 2–associated cytokines. Thus, antigen targeting via the human DCIR receptor allows activation of specific CD8+ T-cell immunity.
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Sakaguchi, Nobuo, Satoru Fujimura, and Kazuhiko Kuwahara. "Involvement of GANP in B Cell Activation in T Cell-dependent Antigen Response." Developmental Immunology 9, no. 3 (2002): 169–72. http://dx.doi.org/10.1080/1044667031000137647.
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Adaptive immunity is dependent on proliferation of antigen-driven B cells for clonal expansion in germinal centers (GCs) against T cell-dependent antigens (TD-Ag), accompanied with somatic hypermutation of variable-region gene and class switching of B cell antigen receptors. To study molecular mechanisms for B cell differentiation in GCs, we have identified and studied a 210 kDa GANP protein expressed in GC-B cells. GANP has domains for MCM3-binding and RNA-primase activities and is selectively up-regulated in centrocytes surrounded with follicular dendritic cells (FDCs) upon immunization with TD-Agin vivoand in B cells stimulated with anti-CD40 monoclonal antibodyin vitro, which suggested that GANP plays a certain important role in the maturation of immunoglobulin or selection of B cells in GC during the immune response to TD-Ag. Since this up-regulation has not been detected in T cells in GCs and in Concanavalin A-stimulated T cellsin vitro, selective function of GANP molecule on B cell proliferation and differentiation might exist.
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Koulova, L., E. A. Clark, G. Shu, and B. Dupont. "The CD28 ligand B7/BB1 provides costimulatory signal for alloactivation of CD4+ T cells." Journal of Experimental Medicine 173, no. 3 (March 1, 1991): 759–62. http://dx.doi.org/10.1084/jem.173.3.759.
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Activation via the T lymphocyte cell surface molecule CD28 provides a potent amplification signal for interleukin 2 (IL-2) production in several in vitro systems. The B lymphocyte activation antigen, B7/BB1, is a natural ligand for CD28. Here we investigate the role of CD28 and B7/BB1 in primary activation of CD4+ T lymphocytes stimulated with allogeneic B lymphoblastoid cell lines. A subset of peripheral CD4+ T cells that is unresponsive to crosslinking of CD3/T cell receptor (TCR) with CD3 monoclonal antibody (mAb) does proliferate in response to allogeneic B lymphoblasts. TCR binding to allogeneic major histocompatibility complex antigens was an absolute requirement for activation of these cells because mAbs to either CD3 or human histocompatibility leukocyte antigen (HLA) class II completely inhibited activation. CD28 and B7/BB1 antibodies inhibited T cell proliferation 90% and 84%, respectively. Similar results were obtained with the total CD4+ T lymphocyte population. Crosslinking of HLA-DR antigens on small, resting B cells induced rapid expression of B7/BB1, which peaked at 6 h and returned to baseline levels within 18 h. These data demonstrate that CD28-B7/BB1 binding provides an important early second signal for alloactivation of CD4+ T lymphocyte by B lymphoblasts. The results also suggest that T cells interacting with allogeneic resting B cells may induce B7/BB1 expression in the alloantigen-presenting cell as a consequence of interaction between the TCR and class II molecules.
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Höglund, Petter, Justine Mintern, Caroline Waltzinger, William Heath, Christophe Benoist, and Diane Mathis. "Initiation of Autoimmune Diabetes by Developmentally Regulated Presentation of Islet Cell Antigens in the Pancreatic Lymph Nodes." Journal of Experimental Medicine 189, no. 2 (January 18, 1999): 331–39. http://dx.doi.org/10.1084/jem.189.2.331.
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Little is known about the events triggering lymphocyte invasion of the pancreatic islets in prelude to autoimmune diabetes. For example, where islet-reactive T cells first encounter antigen has not been identified. We addressed this issue using BDC2.5 T cell receptor transgenic mice, which express a receptor recognizing a natural islet beta cell antigen. In BDC2.5 animals, activated T cells were found only in the islets and the lymph nodes draining them, and there was a close temporal correlation between lymph node T cell activation and islet infiltration. When naive BDC2.5 T cells were transferred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insulitis was detectable. Surprisingly, proliferation was not seen in 10-day-old recipients. This age-dependent dichotomy was reproduced in a second transfer system based on an unrelated antigen artificially expressed on beta cells. We conclude that beta cell antigens are transported specifically to pancreatic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via molecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may be the root of a first “checkpoint” in diabetes progression.
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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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Fleischer, B., and H. Schrezenmeier. "T cell stimulation by staphylococcal enterotoxins. Clonally variable response and requirement for major histocompatibility complex class II molecules on accessory or target cells." Journal of Experimental Medicine 167, no. 5 (May 1, 1988): 1697–707. http://dx.doi.org/10.1084/jem.167.5.1697.
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Staphylococcal enterotoxins (SE) are the most potent mitogens for T lymphocytes known; concentrations of less than 10(-9) M are sufficient for T cell activation. The mechanism of T cell activation by SE is unknown. We have used cloned human cytotoxic and proliferative T lymphocytes to dissect the molecular mechanism of T cell activation by SE. With rare exceptions, all TCR alpha/beta chain-expressing T cell clones of CD4+ or CD8+ phenotype, as well as CD4-8- TCR alpha/beta chain negative chain-expressing T lymphocyte clones, respond with proliferation and/or cytotoxicity to SE. For triggering of all these clones, the presence of autologous or allogeneic MHC class II molecules on accessory or target cells is necessary. This requirement for class II antigens is not due to an immunological recognition of processed SE, since inhibition of antigen processing has no influence on the T cell response to SE. SE acts on the T cells directly since (a) they stimulate a rise in intracellular calcium concentration in T cell lines or purified T cells, and (b) accessory cells can be replaced by phorbolesters in the proliferative activation of resting T cells by SE. Furthermore, the T cell response to SE shows extensive clonal heterogeneity. These results suggest that SE are functionally bivalent mitogens binding highly selectively to HLA class II molecules and the TCR. Thus, compared with other polyclonal T cell activating agents, activation with SE most closely mimicks the physiological way of MHC-restricted antigen recognition by T lymphocytes.
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Jahng, Alex W., Igor Maricic, Brian Pedersen, Nicolas Burdin, Olga Naidenko, Mitchell Kronenberg, Yasuhiko Koezuka, and Vipin Kumar. "Activation of Natural Killer T Cells Potentiates or Prevents Experimental Autoimmune Encephalomyelitis." Journal of Experimental Medicine 194, no. 12 (December 17, 2001): 1789–99. http://dx.doi.org/10.1084/jem.194.12.1789.
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Natural killer (NK) T cells recognize lipid antigens in the context of the major histocompatibility complex (MHC) class 1–like molecule CD1 and rapidly secrete large amounts of the cytokines interferon (IFN)-γ and interleukin (IL)-4 upon T cell receptor (TCR) engagement. We have asked whether NK T cell activation influences adaptive T cell responses to myelin antigens and their ability to cause experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. While simultaneous activation of NK T cells with the glycolipid α-galactosylceramide (α-GalCer) and myelin-reactive T cells potentiates EAE in B10.PL mice, prior activation of NK T cells protects against disease. Exacerbation of EAE is mediated by an enhanced T helper type 1 (Th1) response to myelin basic protein and is lost in mice deficient in IFN-γ. Protection is mediated by immune deviation of the anti-myelin basic protein (MBP) response and is dependent upon the secretion of IL-4. The modulatory effect of α-GalCer requires the CD1d antigen presentation pathway and is dependent upon the nature of the NK T cell response in B10.PL or C57BL/6 mice. Because CD1 molecules are nonpolymorphic and remarkably conserved among different species, modulation of NK T cell activation represents a target for intervention in T cell–mediated autoimmune diseases.
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Dzierszinski, Florence, Marion Pepper, Jason S. Stumhofer, David F. LaRosa, Emma H. Wilson, Laurence A. Turka, Sandra K. Halonen, Christopher A. Hunter, and David S. Roos. "Presentation of Toxoplasma gondii Antigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells." Infection and Immunity 75, no. 11 (September 10, 2007): 5200–5209. http://dx.doi.org/10.1128/iai.00954-07.
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ABSTRACT Challenge with the intracellular protozoan parasite Toxoplasma gondii induces a potent CD8+ T-cell response that is required for resistance to infection, but many questions remain about the factors that regulate the presentation of major histocompatibility complex class I (MHC-I)-restricted parasite antigens and about the role of professional and nonprofessional accessory cells. In order to address these issues, transgenic parasites expressing ovalbumin (OVA), reagents that track OVA/MHC-I presentation, and OVA-specific CD8+ T cells were exploited to compare the abilities of different infected cell types to stimulate CD8+ T cells and to define the factors that contribute to antigen processing. These studies reveal that a variety of infected cell types, including hematopoietic and nonhematopoietic cells, are capable of activating an OVA-specific CD8+ T-cell hybridoma, and that this phenomenon is dependent on the transporter associated with antigen processing and requires live T. gondii. Several experimental approaches indicate that T-cell activation is a consequence of direct presentation by infected host cells rather than cross-presentation. Surprisingly, nonprofessional antigen-presenting cells (APCs) were at least as efficient as dendritic cells at activating this MHC-I-restricted response. Studies to assess whether these cells are involved in initiation of the CD8+ T-cell response to T. gondii in vivo show that chimeric mice expressing MHC-I only in nonhematopoietic compartments are able to activate OVA-specific CD8+ T cells upon challenge. These findings associate nonprofessional APCs with the initial activation of CD8+ T cells during toxoplasmosis.
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Fischer, MB, I. Hauber, H. Eggenbauer, V. Thon, E. Vogel, E. Schaffer, J. Lokaj, J. Litzman, HM Wolf, and JW Mannhalter. "A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency." Blood 84, no. 12 (December 15, 1994): 4234–41. http://dx.doi.org/10.1182/blood.v84.12.4234.bloodjournal84124234.
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Common variable immunodeficiency (CVID) is characterized by an impairment of specific antibody production and a decrease in all or selected Ig isotypes. Abnormalities at the level of the B cells, T cells, and antigen-presenting cells have been described. In the present study, we have focused our attention on T-cell activation in CVID. T cells from 15 of 24 patients failed to respond to recall antigens (eg, tetanus toxoid, Escherichia coli). Of these 15 patients, 11 were studied in detail and showed significantly decreased T-cell proliferative responses and/or decreased interleukin-2 and interferon- gamma production on T-cell receptor-mediated stimulation with recall antigens and superantigens (staphylococcal enterotoxins [SE]); however, T-cell response to mitogens (anti-CD3 monoclonal antibody, phytohemagglutinin) was normal. The defect in interleukin-2 and interferon-gamma release on tetanus toxoid stimulation could also be documented in purified CD4 T cells of the patients and was present in patients with high and normal CD8 counts alike. Furthermore, patients' T cells failed to mount a significant elevation in free intracellular calcium (Ca++ flux) in response to superantigen, whereas the response to phorbol myristate acetate and ionomycin, bypassing receptor-mediated signaling, was unimpaired. These results indicate a defect in the early phase of T-cell activation after triggering of the T-cell receptor in a significant subgroup of CVID patients.
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Seitz, Christian M., Verena Kieble, Clara Illi, Selina Reiter, Stefan Grote, Joerg Mittelstaet, Dominik Lock, et al. "Combinatorial Targeting of Multiple Shared Antigens By Adapter-CAR-T Cells (aCAR-Ts) Allows Target Cell Discrimination and Specific Lysis Based on Differential Expression Profiles." Blood 132, Supplement 1 (November 29, 2018): 4543. http://dx.doi.org/10.1182/blood-2018-99-115630.
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Abstract Despite tremendous clinical success of chimeric antigen receptor (CAR) expressing T cell (CAR-T) therapies, targeting B-phenotypic antigens in ALL, CLL, NHL or multiple myeloma, there are still major limitations for broader clinical application. CAR-Ts are capable to generate a specific immune response against defined surface-expressed antigens leading to sustained depletion of target antigen expressing tissues e.g. B cells. While B cell function can be substituted by repetitive IgG infusions, prolonged depletion of vitally essential tissues is not compatible with life. In AML for instance, most promising target antigens are expressed along myeloid lineage differentiation, limiting the therapeutic applicability. Therefore, CAR-Ts targeting essential shared antigens must allow tight regulation of CAR-T function and/or be able to differentiate between cancerous and healthy tissue. To address these issues, we have developed the adapter CAR-T cell (aCAR-T) system. By splitting antigen recognition and CAR-T activation, introducing adapter molecules (AMs), the system allows precise quantitative (on-/off-switch) as well as qualitative (change and combine target antigens) regulation of CAR-T function. aCAR-Ts are based on the unique properties of a novel scFv targeting a "neo"-epitope-like structure consisting of the endogenous vitamin biotin in the context of a specific linker, referred to as linker-label-epitope (LLE). LLEs can be easily conjugated to novel or preexisting AM formats like monoclonal antibodies (mAbs) or mAb fragments in a GMP-compliant manner. We were able to demonstrate that aCAR-Ts allow simultaneous targeting of various antigens ("OR"-gate) , preventing antigen evasion by selection of antigen or epitope-loss variants. In the present study we intended to investigate whether aCAR-Ts are capable to identify and differentiate target cells due to versatile antigen expression profiles ("AND"-gate). In theory, AMs against different target antigens can be assembled on the surface of a target cell , leading to aCAR-T activation independent of the targeted antigens (surface painting) , by binding to the presented LLE-tags. Therefore, combinatorial AMs treatment might allow to translate complex and multiple antigen-dependent target cell identification into an aCAR-T activation. To test this hypothesis, we have generated LLE-AMs against ALL/NHL - (CD10, CD19, CD20, CD22, CD37, CD138, ROR1) and AML - (CD32, CD33, CD38, CD123, CD135, CD305, CLL1) associated antigens. Individual threshold concentrations for aCAR-T activation by different AMs, targeti ng the model cell lines Nalm 6 (ALL), JeKo1 (NHL), HL-60 , U973 and Molm13 ( all AML), have been analyzed. Cut offs were found to be between 10 and 100 pg/ml, dependent on target expression and target cell line. Importantly, combinations of 2, 3 or 5 AMs, targeting different antigens expressed on the same target cell, cause target- cell lysis at concentrations below the activation threshold for single AMs (exemplified for HL-60 in Figure A) . Our results clearly demonstrate an additive effect in combining different AMs to hurdle the activation threshold. Moreover, in a JeKo 1 CD19 and/or CD20 knock out (KO) antigen-loss model, combinations of AMs targeting CD19, CD20 and ROR1 can differentiate between wild type and antigen -1 (CD19 or CD20 KO) or antigen -2 (CD19 and CD20 KO) variants in medi ating target- cell lysis, even though at least one target antigen is expressed. Finally, we found that combinations of CD10, CD19, CD22 and CD138 sufficiently eliminate Nalm-6 BCP-ALL cells, while sparing healthy B cells in co - culture experiments. Similar results were obtained in co - culture experiments of HL-60 AML cells with monocytes, neutrophils as well as CD34- enriched hematopoietic progenitor cells, applying combinations of CD32, CD33, CD38, CD123, CD305 and CLL1. Co - culturing experiments using autologous blasts, monocytes, neutrophils and aCAR-Ts are ongoing. Together, our results indicate that aCAR-Ts in combination with selected AM combinations might have the ability to identify and specifically eliminate cancer cells based on complex antigen expression profiles. This would have major implications for clinical translation, enabling combinatorial therapy, essential to avoid antigen evasion, and the possibility to spare vitally essential tissue from elimination. Figure. Figure. Disclosures Seitz: Miltenyi Biotec: Patents & Royalties, Research Funding. Mittelstaet:Miltenyi Biotec: Employment, Patents & Royalties. Lock:Miltenyi Biotec: Employment. Kaiser:Miltenyi Biotec: Employment, Patents & Royalties. Handgretinger:Miltenyi Biotec: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding. Lang:Miltenyi Biotec: Patents & Royalties, Research Funding. Schlegel:Miltenyi Biotec: Patents & Royalties, Research Funding.
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Alonso-Camino, Vanesa, Seandean Lykke Harwood, Ana Álvarez-Méndez, and Luis Alvarez-Vallina. "Efficacy and toxicity management of CAR-T-cell immunotherapy: a matter of responsiveness control or tumour-specificity?" Biochemical Society Transactions 44, no. 2 (April 11, 2016): 406–11. http://dx.doi.org/10.1042/bst20150286.
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Chimaeric antigen receptor (CAR)-expressing T-cells have demonstrated potent clinical efficacy in patients with haematological malignancies. However, the use of CAR-T-cells targeting solid tumour-associated antigens (TAAs) has been limited by organ toxicities related to activation of T-cell effector functions through the CAR. Most existing CARs recognize TAAs, which are also found in normal tissues. CAR-T-cell-mediated destruction of normal tissues constitutes a major roadblock to CAR-T-cell therapy, and must be avoided or mitigated. There is a broad range of strategies for modulating antigen responsiveness of CAR-T-cells, with varying degrees of complexity. Some of them might ameliorate the acute and chronic toxicities associated with current CAR constructs. However, further embellishments to CAR therapy may complicate clinical implementation and possibly create new immunogenicity issues. In contrast, the development of CARs targeting truly tumour-specific antigens might circumvent on-target/off-tumour toxicities without adding additional complexity to CAR-T-cell therapies, but these antigens have been elusive and may require novel selection strategies for their discovery.
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Vigouroux, Stéphane, Eric Yvon, Hans-Joachim Wagner, Ettore Biagi, Gianpietro Dotti, Uluhan Sili, Cecilia Lira, Cliona M. Rooney, and Malcolm K. Brenner. "Induction of Antigen-Specific Regulatory T Cells following Overexpression of a Notch Ligand by Human B Lymphocytes." Journal of Virology 77, no. 20 (October 15, 2003): 10872–80. http://dx.doi.org/10.1128/jvi.77.20.10872-10880.2003.
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ABSTRACT In mice, activation of the Notch pathway in T cells by antigen-presenting cells overexpressing Notch ligands favors differentiation of regulatory T lymphocytes responsible for antigen-specific tolerance. To determine whether this mechanism operates in human T cells, we used Epstein-Barr virus-positive lymphoblastoid cell lines (EBV-LCL) as our (viral) antigen-presenting cells and overexpressed the Notch ligand Jagged-1 (EBV-LCL J1) by adenoviral transduction. The EBV-LCL J1s were cocultured with autologous T cells, and the proliferative and cytotoxic responses to EBV antigens were measured. Transduction had no effect on EBV-LCL expression of major histocompatibility complex (MHC) antigens or of costimulatory molecules CD80, CD86, and CD40. However, we observed a 35% inhibition of proliferation and a >65% reduction in cytotoxic-T-cell activity, and interleukin 10 production was increased ninefold. These EBV-LCL J1-stimulated T lymphocytes act as antigen-specific regulatory cells, since their addition to fresh autologous T cells cultured with autologous nontransduced EBV-LCL cells significantly inhibited both proliferation and cytotoxic effector function. Within the inhibitory population, CD4+CD25+ and CD8+CD25− T cells had the greatest activity. This inhibition appears to be antigen-specific, since responses to Candida and cytomegalovirus antigens were unaffected. Hence, transgenic expression of Jagged-1 by antigen-presenting cells can induce antigen-specific regulatory T cells in humans and modify immune responses to viral antigens.
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van Dinther, Dieke, Miguel Lopez Venegas, Henrike Veninga, Katarzyna Olesek, Leoni Hoogterp, Mirjam Revet, Martino Ambrosini, et al. "Activation of CD8+ T Cell Responses after Melanoma Antigen Targeting to CD169+ Antigen Presenting Cells in Mice and Humans." Cancers 11, no. 2 (February 5, 2019): 183. http://dx.doi.org/10.3390/cancers11020183.
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The lack of tumor-reactive T cells is one reason why immune checkpoint inhibitor therapies still fail in a significant proportion of melanoma patients. A vaccination that induces melanoma-specific T cells could potentially enhance the efficacy of immune checkpoint inhibitors. Here, we describe a vaccination strategy in which melanoma antigens are targeted to mouse and human CD169 and thereby induce strong melanoma antigen-specific T cell responses. CD169 is a sialic acid receptor expressed on a subset of mouse splenic macrophages that captures antigen from the blood and transfers it to dendritic cells (DCs). In human and mouse spleen, we detected CD169+ cells at an equivalent location using immunofluorescence microscopy. Immunization with melanoma antigens conjugated to antibodies (Abs) specific for mouse CD169 efficiently induced gp100 and Trp2-specific T cell responses in mice. In HLA-A2.1 transgenic mice targeting of the human MART-1 peptide to CD169 induced strong MART-1-specific HLA-A2.1-restricted T cell responses. Human gp100 peptide conjugated to Abs specific for human CD169 bound to CD169-expressing monocyte-derived DCs (MoDCs) and resulted in activation of gp100-specific T cells. Together, these data indicate that Ab-mediated antigen targeting to CD169 is a potential strategy for the induction of melanoma-specific T cell responses in mice and in humans.
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Kitano, Masahiro, Chihiro Yamazaki, Akiko Takumi, Takashi Ikeno, Hiroaki Hemmi, Noriko Takahashi, Kanako Shimizu, et al. "Imaging of the cross-presenting dendritic cell subsets in the skin-draining lymph node." Proceedings of the National Academy of Sciences 113, no. 4 (January 11, 2016): 1044–49. http://dx.doi.org/10.1073/pnas.1513607113.
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Dendritic cells (DCs) are antigen-presenting cells specialized for activating T cells to elicit effector T-cell functions. Cross-presenting DCs are a DC subset capable of presenting antigens to CD8+ T cells and play critical roles in cytotoxic T-cell–mediated immune responses to microorganisms and cancer. Although their importance is known, the spatiotemporal dynamics of cross-presenting DCs in vivo are incompletely understood. Here, we study the T-cell zone in skin-draining lymph nodes (SDLNs) and find it is compartmentalized into regions for CD8+ T-cell activation by cross-presenting DCs that express the chemokine (C motif) receptor 1 gene, Xcr1 and for CD4+ T-cell activation by CD11b+ DCs. Xcr1-expressing DCs in the SDLNs are composed of two different populations: migratory (CD103hi) DCs, which immigrate from the skin, and resident (CD8αhi) DCs, which develop in the nodes. To characterize the dynamic interactions of these distinct DC populations with CD8+ T cells during their activation in vivo, we developed a photoconvertible reporter mouse strain, which permits us to distinctively visualize the migratory and resident subsets of Xcr1-expressing DCs. After leaving the skin, migratory DCs infiltrated to the deep T-cell zone of the SDLNs over 3 d, which corresponded to their half-life in the SDLNs. Intravital two-photon imaging showed that after soluble antigen immunization, the newly arriving migratory DCs more efficiently form sustained conjugates with antigen-specific CD8+ T cells than other Xcr1-expressing DCs in the SDLNs. These results offer in vivo evidence for differential contributions of migratory and resident cross-presenting DCs to CD8+ T-cell activation.
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Risau, W., B. Engelhardt, and H. Wekerle. "Immune function of the blood-brain barrier: incomplete presentation of protein (auto-)antigens by rat brain microvascular endothelium in vitro." Journal of Cell Biology 110, no. 5 (May 1, 1990): 1757–66. http://dx.doi.org/10.1083/jcb.110.5.1757.
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The endothelial blood-brain barrier (BBB) has a critical role in controlling lymphocyte traffic into the central nervous system (CNS), both in physiological immunosurveillance, and in its pathological aberrations. The intercellular signals that possibly could induce lymphocytes to cross the BBB include immunogenic presentation of protein (auto-)antigens by BBB endothelia to circulating T lymphocytes. This concept has raised much, though controversial, attention. We approached this problem by analyzing in vitro immunospecific interactions between clonal rat T lymphocyte lines with syngeneic, stringently purified endothelial monolayer cultures from adult brain micro-vessels. The rat brain endothelia (RBE) were established from rat brain capillaries using double collagenase digestion, density gradient fractionation and selective cytolysis of contaminating pericytes by anti-Thy 1.1 antibodies and complement. Incubation with interferon-gamma in most of the brain-derived endothelial cells induced Ia-antigens in the cytoplasm and on the cell surface in some of the cells. Before the treatment, the cells were completely Ia-negative. Pericytes were unresponsive to IFN-gamma treatment. When confronted with syngeneic T cell lines specific for protein (auto-)antigens (e.g., ovalbumin and myelin basic protein, MBP), RBE were completely unable to induce antigen-specific proliferation of syngeneic T lymphocytes irrespective of pretreatment with IFN-gamma and of cell density. RBE were inert towards the T cells, and did not suppress T cell activation induced by other "professional" antigen presenting cells (APC) such as thymus-derived dendritic cells or macrophages. IFN-gamma-treated RBE were, however, susceptible to immunospecific T cell killing. They were lysed by MBP-specific T cells in the presence of the specific antigen or Con A. Antigen dependent lysis was restricted by the appropriate (MHC) class II product. We conclude that the interaction of brain endothelial cells with encephalitogenic T lymphocytes may involve recognition of antigen in the molecular context of relevant MHC products, but that this interaction per se is insufficient to initiate the full T cell activation program.
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Snapper, C. M., T. M. McIntyre, R. Mandler, L. M. Pecanha, F. D. Finkelman, A. Lees, and J. J. Mond. "Induction of IgG3 secretion by interferon gamma: a model for T cell-independent class switching in response to T cell-independent type 2 antigens." Journal of Experimental Medicine 175, no. 5 (May 1, 1992): 1367–71. http://dx.doi.org/10.1084/jem.175.5.1367.
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T cell-independent type 2 (TI-2), in contrast to T-dependent, antigens stimulate the production of murine IgG3. To investigate a possible role for cytokines in mediating the induction of this IgG subclass, we established an in vitro polyclonal model system for studying TI-2 antigen-mediated B cell activation by using dextran-conjugated anti-IgD antibody (alpha delta-dex). We demonstrate that interferon gamma (IFN-gamma) stimulates, and interleukin 4 inhibits, the expression of IgG3 by alpha delta-dexactivated cells. The production of IFN-gamma by non-T cells in response to bacterial products, possibly capsular polysaccharides, may provide an explanation underlying the ability of TI antigens, which are unable to directly stimulate T cell-derived cytokines to induce Ig isotype switching.