scholarly journals Role of Antigen-Presenting Cells in Mediating Tolerance and Autoimmunity

1999 ◽  
Vol 191 (11) ◽  
pp. 2021-2028 ◽  
Author(s):  
Kristine M. Garza ◽  
Steven M. Chan ◽  
Rakesh Suri ◽  
Linh T. Nguyen ◽  
Bernhard Odermatt ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Islet Cells ◽  
Antigen Presenting Cells ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Activation Markers ◽  
Insulin Promoter ◽  
Lymphocyte Activity ◽  
Antigen Presenting

The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic β-islet cells together with T cells expressing an LCMV-gp–specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.

CD3ζ and CD28 down-modulation on CD8 T cells during viral infection

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1021-1029 ◽  
Author(s):  
Linda A. Trimble ◽  
Lawrence W. Kam ◽  
Rachel S. Friedman ◽  
Zhan Xu ◽  
Judy Lieberman
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Receptor ◽  
Activation Markers ◽  
Barr Virus ◽  
Chronic Antigenic Stimulation ◽  
Epstein Barr

Abstract Down-modulation of CD3ζ expression on CD8 T lymphocytes occurs, independently of other T-cell receptor (TCR)-CD3 components, in tumor-infiltrating lymphocytes, human immunodeficiency virus infection, and autoimmune disease. These associations suggest that it might be related to chronic antigenic stimulation. CD3ζ down-modulation was found, however, in CD8 T cells that proliferate in response to acute viral infections. In 3 otherwise healthy donors with acute gastroenteritis, infectious mononucleosis, and Epstein–Barr virus/cytomegalovirus/mononucleosis, 30% to 60% of circulating CD8 T cells had down-modulated CD3ζ to below the level of detection. The CD3ζ-T cells were also CD28− but expressed the activation markers HLA-DR and CD57. CD3ζ–CD28– T cells are effector CTL because they express perforin and produce IFN-γ, but not IL-2, on activation and contain the viral-specific cytotoxic T lymphocyte (CTL). However, CD3ζ–CD28–T cells generally do not express CD25 after anti-CD3 and anti-CD28 stimulation and are not cytotoxic until they are cultured with IL-2 overnight. Cytotoxicity coincides with the re-expression of CD3ζ but not CD28. Down-modulation of CD3ζ and CD28 on effector CTL may control CTL triggering and proliferation to prevent immunopathogenesis.

scholarly journals Cd8− T Cell Transfectants That Express a High Affinity T Cell Receptor Exhibit Enhanced Peptide-Dependent Activation

2001 ◽  
Vol 194 (8) ◽  
pp. 1043-1052 ◽  
Author(s):  
Phillip D. Holler ◽  
Alice R. Lim ◽  
Bryan K. Cho ◽  
Laurie A. Rund ◽  
David M. Kranz
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cytotoxic T Lymphocyte ◽  
Cell Activity ◽  
Cell Receptor ◽  
Wild Type ◽  
High Affinity ◽  
Antigen Presenting

T cells are activated by binding of the T cell receptor (TCR) to a peptide-major histocompatibility complex (MHC) complex (pMHC) expressed on the surface of antigen presenting cells. Various models have predicted that activation is limited to a narrow window of affinities (or dissociation rates) for the TCR–pMHC interaction and that above or below this window, T cells will fail to undergo activation. However, to date there have not been TCRs with sufficiently high affinities in order to test this hypothesis. In this report we examined the activity of a CD8-negative T cell line transfected with a high affinity mutant TCR (KD = 10 nM) derived from cytotoxic T lymphocyte clone 2C by in vitro engineering. The results show that despite a 300-fold higher affinity and a 45-fold longer off-rate compared with the wild-type TCR, T cells that expressed the mutant TCRs were activated by peptide. In fact, activation could be detected at significantly lower peptide concentrations than with T cells that expressed the wild-type TCR. Furthermore, binding and functional analyses of a panel of peptide variants suggested that pMHC stability could account for apparent discrepancies between TCR affinity and T cell activity observed in several prior studies.

scholarly journals Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells

2015 ◽  
Vol 212 (8) ◽  
pp. 1153-1169 ◽  
Author(s):  
Jasmin Herz ◽  
Kory R. Johnson ◽  
Dorian B. McGavern
Keyword(s):  
T Cells ◽  
Nervous System ◽  
Antigen Presenting Cells ◽  
Lymphocytic Choriomeningitis ◽  
Neurological Dysfunction ◽  
Persistently Infected ◽  
Barr Virus ◽  
Inflammatory Monocytes ◽  
Antigen Presenting ◽  
Antiviral T Cells

Several viruses can infect the mammalian nervous system and induce neurological dysfunction. Adoptive immunotherapy is an approach that involves administration of antiviral T cells and has shown promise in clinical studies for the treatment of peripheral virus infections in humans such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus, among others. In contrast, clearance of neurotropic infections is particularly challenging because the central nervous system (CNS) is relatively intolerant of immunopathological reactions. Therefore, it is essential to develop and mechanistically understand therapies that noncytopathically eradicate pathogens from the CNS. Here, we used mice persistently infected from birth with lymphocytic choriomeningitis virus (LCMV) to demonstrate that therapeutic antiviral T cells can completely purge the persistently infected brain without causing blood–brain barrier breakdown or tissue damage. Mechanistically, this is accomplished through a tailored release of chemoattractants that recruit antiviral T cells, but few pathogenic innate immune cells such as neutrophils and inflammatory monocytes. Upon arrival, T cells enlisted the support of nearly all brain-resident myeloid cells (microglia) by inducing proliferation and converting them into CD11c+ antigen-presenting cells (APCs). Two-photon imaging experiments revealed that antiviral CD8+ and CD4+ T cells interacted directly with CD11c+ microglia and induced STAT1 signaling but did not initiate programmed cell death. We propose that noncytopathic CNS viral clearance can be achieved by therapeutic antiviral T cells reliant on restricted chemoattractant production and interactions with apoptosis-resistant microglia.

scholarly journals Bone Marrow–Derived Antigen-Presenting Cells Are Required for the Generation of Cytotoxic T Lymphocyte Responses to Viruses and Use Transporter Associated with Antigen Presentation (Tap)-Dependent and -Independent Pathways of Antigen Presentation

2000 ◽  
Vol 192 (8) ◽  
pp. 1143-1150 ◽  
Author(s):  
Luis J. Sigal ◽  
Kenneth L. Rock
Keyword(s):  
Bone Marrow ◽  
Antigen Presentation ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Antigen Presenting Cells ◽  
Lymphocytic Choriomeningitis ◽  
Ctl Response ◽  
Lymphocyte Responses ◽  
Antigen Presenting ◽  
Ctl Responses

Bone marrow (BM)-derived professional antigen-presenting cells (pAPCs) are required for the generation of cytotoxic T lymphocyte (CTL) responses to vaccinia virus and poliovirus. Furthermore, these BM-derived pAPCs require a functional transporter associated with antigen presentation (TAP). In this report we analyze the requirements for BM-derived pAPCs and TAP in the initiation of CTL responses to lymphocytic choriomeningitis virus (LCMV) and influenza virus (Flu). Our results indicate a requirement for BM-derived pAPCs for the CTL responses to these viruses. However, we found that the generation of CTLs to one LCMV epitope (LCMV nucleoprotein 396–404) was dependent on BM-derived pAPCs but, surprisingly, TAP independent. The study of the CTL response to Flu confirmed the existence of this BM-derived pAPC-dependent/TAP-independent CTL response and indicated that the TAP-independent pathway is ∼10–300-fold less efficient than the TAP-dependent pathway.

scholarly journals The combination of anti-B7 monoclonal antibody and cyclosporin A induces alloantigen-specific anergy during a primary mixed lymphocyte reaction.

1994 ◽  
Vol 179 (2) ◽  
pp. 715-720 ◽  
Author(s):  
S W Van Gool ◽  
M de Boer ◽  
J L Ceuppens
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Cyclosporin A ◽  
Mixed Lymphocyte Reaction ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Third Party ◽  
Clonal Deletion ◽  
Antigen Presenting

Interaction of CD28/CTLA-4 on T cells with B7 on antigen-presenting cells constitutes an important costimulatory signal for T cells and is responsible for cyclosporin A-resistant interleukin 2 (IL-2) gene expression and potentially also for prevention of anergy induction after T cell receptor triggering. In this paper, we demonstrate that addition of a monoclonal antibody to B7, which blocks B7-CD28/CTLA-4 interaction, and of cyclosporin A together, but not separately, to a primary mixed lymphocyte reaction of freshly isolated human T cells towards a human B cell line, induces nonresponsiveness of alloantigen-specific cytotoxic T lymphocyte precursors, whereas reactivity to a third party stimulator is intact. Nonresponsiveness could be reversed by culture in IL-2, indicating that anergy, and not clonal deletion, is responsible for this phenomenon. Our finding opens important perspectives for the development of new therapeutic strategies in transplantation.

CD3ζ and CD28 down-modulation on CD8 T cells during viral infection

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1021-1029 ◽  
Author(s):  
Linda A. Trimble ◽  
Lawrence W. Kam ◽  
Rachel S. Friedman ◽  
Zhan Xu ◽  
Judy Lieberman
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Receptor ◽  
Activation Markers ◽  
Barr Virus ◽  
Chronic Antigenic Stimulation ◽  
Epstein Barr

Down-modulation of CD3ζ expression on CD8 T lymphocytes occurs, independently of other T-cell receptor (TCR)-CD3 components, in tumor-infiltrating lymphocytes, human immunodeficiency virus infection, and autoimmune disease. These associations suggest that it might be related to chronic antigenic stimulation. CD3ζ down-modulation was found, however, in CD8 T cells that proliferate in response to acute viral infections. In 3 otherwise healthy donors with acute gastroenteritis, infectious mononucleosis, and Epstein–Barr virus/cytomegalovirus/mononucleosis, 30% to 60% of circulating CD8 T cells had down-modulated CD3ζ to below the level of detection. The CD3ζ-T cells were also CD28− but expressed the activation markers HLA-DR and CD57. CD3ζ–CD28– T cells are effector CTL because they express perforin and produce IFN-γ, but not IL-2, on activation and contain the viral-specific cytotoxic T lymphocyte (CTL). However, CD3ζ–CD28–T cells generally do not express CD25 after anti-CD3 and anti-CD28 stimulation and are not cytotoxic until they are cultured with IL-2 overnight. Cytotoxicity coincides with the re-expression of CD3ζ but not CD28. Down-modulation of CD3ζ and CD28 on effector CTL may control CTL triggering and proliferation to prevent immunopathogenesis.

scholarly journals Microfluidics sorting enables the isolation of an intact cellular pair complex of CD8+ T cells and antigen-presenting cells in a cognate antigen recognition-dependent manner

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252666
Author(s):  
Soichiro Kuwabara ◽  
Yoshihiko Tanimoto ◽  
Mie Okutani ◽  
Meng Jie ◽  
Yasunari Haseda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Specific Interaction ◽  
Antigen Presenting Cells ◽  
Cell Receptor ◽  
Dependent Manner ◽  
Cell Sorter ◽  
Cognate Antigen ◽  
Antigen Presenting ◽  
Cellular Complex

Adaptive immune responses begin with cognate antigen presentation-dependent specific interaction between T cells and antigen-presenting cells. However, there have been limited reports on the isolation and analysis of these cellular complexes of T cell-antigen-presenting cell (T/APC). In this study, we successfully isolated intact antigen-specific cellular complexes of CD8+ T/APC by utilizing a microfluidics cell sorter. Using ovalbumin (OVA) model antigen and OT-I-derived OVA-specific CD8+ T cells, we analyzed the formation of antigen-specific and antigen-non-specific T/APC cellular complexes and revealed that the antigen-specific T/APC cellular complex was highly stable than the non-specific one, and that the intact antigen-specific T/APC complex can be retrieved as well as enriched using a microfluidics sorter, but not a conventional cell sorter. The single T/APC cellular complex obtained can be further analyzed for the sequences of T cell receptor Vα and Vβ genes as well as cognate antigen information simultaneously. These results suggested that this approach can be applied for other antigen and CD8+ T cells of mice and possibly those of humans. We believe that this microfluidics sorting method of the T/APC complex will provide useful information for future T cell immunology research.

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