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.

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.

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 Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1.

1993 ◽  
Vol 177 (1) ◽  
pp. 165-173 ◽  
Author(s):  
P Tan ◽  
C Anasetti ◽  
J A Hansen ◽  
J Melrose ◽  
M Brunvand ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Primary Cultures ◽  
Interleukin 2 ◽  
Lymphocyte Activation ◽  
Cell Receptor ◽  
T Cell Proliferation ◽  
Natural Ligand ◽  
Antigen Presenting

The specificity of T lymphocyte activation is determined by engagement of the T cell receptor (TCR) by peptide/major histocompatibility complexes expressed on the antigen-presenting cell (APC). Lacking costimulation by accessory molecules on the APC, T cell proliferation does not occur and unresponsiveness to subsequent antigenic stimulus is induced. The B7/BB1 receptor on APCs binds CD28 and CTLA-4 on T cells, and provides a costimulus for T cell proliferation. Here, we show that prolonged, specific T cell hyporesponsiveness to antigenic restimulation is achieved by blocking the interaction between CD28 and B7/BB1 in human mixed leukocyte culture (MLC). Secondary T cell proliferative responses to specific alloantigen were inhibited by addition to the primary culture of monovalent Fab fragments of anti-CD28 monoclonal antibody (mAb) 9.3, which block interaction of CD28 with B7/BB1 without activating T cells. Hypo-responsiveness was also induced in MLC by CTLA4Ig, a chimeric immunoglobulin fusion protein incorporating the extracellular domain of CTLA-4 with high binding avidity for B7/BB1. Cells previously primed could also be made hyporesponsive, if exposed to alloantigen in the presence of CTLA4Ig. Maximal hyporesponsiveness was achieved in MLC after 2 d of incubation with CTLA4Ig, and was maintained for at least 27 d after removal of CTLA4Ig. Accumulation of interleukin 2 (IL-2) and interferon gamma but not IL-4 mRNA was blocked by CTLA4Ig in T cells stimulated by alloantigen. Antigen-specific responses could be restored by addition of exogenous IL-2 at the time of the secondary stimulation. Addition to primary cultures of the intact bivalent anti-CD28 mAb 9.3, or B7/BB1+ transfected CHO cells or exogenous IL-2, abrogated induction of hyporesponsiveness by CTLA4Ig. These data indicate that interaction of CD28 with B7/BB1 during TCR engagement with antigen is required to maintain T cell competence and that blocking such interaction can result in a state of T cell hyporesponsiveness.

scholarly journals Interleukin 2, but Not Other Common γ Chain–Binding Cytokines, Can Reverse the Defect in Generation of Cd4 Effector T Cells from Naive T Cells of Aged Mice

1999 ◽  
Vol 190 (7) ◽  
pp. 1013-1024 ◽  
Author(s):  
Laura Haynes ◽  
Phyllis-Jean Linton ◽  
Sheri M. Eaton ◽  
Susan L. Tonkonogy ◽  
Susan L. Swain
Keyword(s):  
T Cells ◽  
Early Stage ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cd4 Cells ◽  
Aged Mice ◽  
Proliferation And Differentiation ◽  
Two Stages ◽  
Antigen Presenting ◽  
Young Mice

Development of effectors from naive CD4 cells occurs in two stages. The early stage involves activation and limited proliferation in response to T cell receptor (TCR) stimulation by antigen and costimulatory antigen presenting cells, whereas the later stage involves proliferation and differentiation in response to growth factors. Using a TCR-transgenic (Tg+) model, we have examined the effect of aging on effector generation and studied the ability of γc signaling cytokines to reverse this effect. Our results indicate that responding naive CD4 cells from aged mice, compared with cells from young mice, make less interleukin (IL)-2, expand poorly between days 3 to 5, and give rise to fewer effectors with a less activated phenotype and reduced ability to produce cytokines. When exogenous IL-2 or other γc signaling cytokines are added during effector generation, the Tg+ cells from both young and aged mice proliferate vigorously. However, IL-4, IL-7, and IL-15 all fail to restore efficient effector production. Only effectors from aged mice generated in the presence of IL-2 are able to produce IL-2 in amounts equivalent to those produced by effectors generated from young mice, suggesting that the effect of aging on IL-2 production is reversible only in the presence of exogenous IL-2.

scholarly journals T cell receptor-mediated selection of functional rat CD8 T cells from defined immature thymocyte precursors in short-term suspension culture.

1991 ◽  
Vol 173 (3) ◽  
pp. 561-568 ◽  
Author(s):  
T Hünig ◽  
R Mitnacht
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cytotoxic T Lymphocyte ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Double Positive ◽  
Homogeneous Population

Recent results have indicated that positive and negative repertoire selection act on the major population of CD4,8 double-positive (DP) thymocytes that express 5-10-fold less T cell receptor (TCR) than mature T cells (i.e., they are TCRlow). Since DP cells obtained ex vivo are heterogeneous with regard to their stage within thymic selection, a homogeneous population of virgin DP cells suitable for selection studies was generated in vitro from their immediate precursors, the CD8 single-positive (SP) immature blast cells. To mimic TCR-mediated selection signals, these virgin DP cells were then cultured for another 2 d in the presence of immobilized anti-TCR monoclonal antibodies with or without interleukin 2 (IL-2). Daily monitoring of recovery and phenotype showed that without TCR stimulation, the cells remained DP and became small, TCRlow cells that were lost with a half-life of 1 d, regardless of the presence of IL-2. TCR stimulation resulted in rapid downregulation of CD4 and CD8, maintenance of a larger cell size, and induction of the CD53 antigen that marks mature and CD4,8 double-negative rat thymocytes. In the absence of IL-2, viability decreased as rapidly as without TCR stimulation. Addition of IL-2 rescued TCR-stimulated virgin DP cells and prevented CD8 downregulation, so that 50-80% of input DP cells were recovered after 2 d as CD4-8+53+ cells. After release from modulation, these in vitro generated CD8 SP cells quantitatively upregulated the TCR to the TCRhigh phenotype and were readily induced to proliferate and exhibit cytotoxic T lymphocyte (CTL) activity in a polyclonal readout. Evidence is presented implicating an IL-2 receptor (IL-2R) not containing the p55 chain (i.e., most likely the p70 intermediate affinity IL-2R) in the TCR plus IL-2-driven in vitro differentiation of virgin DP cells towards the mature CD8 SP phenotype.

scholarly journals Progress in Research on Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) and Bladder Cancer

2019 ◽  
pp. 1-7 ◽  
Author(s):  
Wei-Ming Fang ◽  
Chun Chen
Keyword(s):  
Monoclonal Antibody ◽  
Bladder Cancer ◽  
T Cells ◽  
T Lymphocyte ◽  
First Generation ◽  
Cytotoxic T Lymphocyte ◽  
Inhibit Tumor Growth ◽  
Igg1 Monoclonal Antibody ◽  
Antigen Presenting ◽  
Important Therapeutic Target

Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) was first discovered in 1987 and confirmed to be a protein that is mainly expressed on the surface of activated lymphocytes. CTLA-4 is expressed on the surface of T cells and binds to B7 expressed on antigen presenting cells(APCs) to potentially play a role in inhibiting lymphocyte proliferation. Inhibitors of CTLA-4 were developed to promote the anti-tumor effects of T cells and inhibit tumor growth. CTLA-4, as an immune checkpoint, has been realized as an important therapeutic target in bladder cancer. Two main CTLA-4 inhibitors are currently used: ipilimumab is a first-generation IgG1 monoclonal antibody that targets CTLA-4, and it is completely synthetic; tremelimumab, representing another class of CTLA-4 inhibitors, is a monoclonal antibody against CTLA-4 that acts similarly to ipilimumab and binds specifically to CTLA-4. The two types of CTLA-4 inhibitors were found to improve the treatment effect in patients with bladder cancer in comparison to conventional agents. To review this topic, we searched recently published related articles.

scholarly journals Absence of the Lyt-2-,L3T4+ lineage of T cells in mice treated neonatally with anti-I-A correlates with absence of intrathymic I-A-bearing antigen-presenting cell function.

1985 ◽  
Vol 161 (5) ◽  
pp. 1029-1047 ◽  
Author(s):  
A M Kruisbeek ◽  
J J Mond ◽  
B J Fowlkes ◽  
J A Carmen ◽  
S Bridges ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Class Ii ◽  
Antibody Treatment ◽  
Cell Functions ◽  
Antigen Presenting

In an effort to elucidate the role of intrathymic Ia-bearing antigen-presenting cells (APC) on the development of the class II-restricted T cell repertoire, we examined the effect of neonatal anti-I-A treatment on both intrathymic and splenic APC function; on the generation of Lyt-2-,L3T4+, Lyt-2+,L3T4-, and Lyt-2+,L3T4+ T cells; and on the development of class I- and class II-specific T cell functions. Both the thymus and the spleen are completely devoid of Lyt-2-,L3T4+ T cells in young mice treated from birth with anti-I-A, and also lack functions associated with this subset, i.e., alloantigen-specific interleukin 2 production (present report), allo-class II-specific and self-class II-restricted T cell proliferative responses, and helper cell function for the generation of cytotoxic T lymphocyte responses (18). Development of the Lyt-2+,L3T4- subset proceeds undisturbed in these mice, in accord with the previously reported normal levels of cytotoxic T lymphocyte precursors (18). The thymus contains normal numbers of the immature cortical Lyt-2+,L3T4+ cells, indicating that acquisition of the L3T4 marker, in and of itself, is not influenced by anti-I-A treatment. This striking absence of the lineage of T cells responsible for class II-specific T cell functions is correlated with absence of thymic APC function for class II-restricted T cell clones. When anti-I-A-treated mice are allowed to recover from the antibody treatment, splenic and thymic APC function return to normal in 2-3 wk, and thymic Lyt-2-,L3T4+ T cell numbers and functions reappear before such cells are detectable in the spleen. Collectively, these findings suggest that development of the Lyt-2-,L3T4+ lineage of class II-specific T cells is entirely dependent on functional I-A-bearing APC cells in the thymus. In addition, the presence of normal levels of Lyt-2+,L3T4-T cells argues that generation of the two major subsets of T cells (i.e., Lyt-2+,L3T4- and Lyt-2-,L3T4+) occurs through separate events, involving unique sites of interactions between precursor T cells and nonlymphoid major histocompatibility complex-bearing thymus cells.

Synergy between cyclosporin A and a monoclonal antibody to B7 in blocking alloantigen-induced T-cell activation

Blood ◽  
1994 ◽  
Vol 83 (1) ◽  
pp. 176-183
Author(s):  
SW Van Gool ◽  
JL Ceuppens ◽  
H Walter ◽  
M de Boer
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Cyclosporin A ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Barr Virus ◽  
Epstein Barr

Costimulatory signals are absolutely required for T-cell activation after T-cell receptor/major histocompatibility complex-peptide interaction. So far, the best-known candidate essential costimulatory signal is mediated by interaction of CD28 on T cells with B7 on antigen- presenting cells. Using an allogeneic B7+ Epstein-Barr virus- transformed B-cell line as stimulator, we found that addition of a monoclonal antibody (MoAb) to B7 that efficiently blocks B7-CD28 interaction only partially inhibited proliferation and interleukin-2 (IL-2) production in primary and secondary mixed lymphocyte reactions (MLR), whereas the generation of cytotoxic T lymphocytes (CTL) was not affected. Inhibition of primary or secondary MLR-induced T-cell activation with cyclosporin A (CsA) at nontoxic concentrations also was never complete. However, the combination of CsA and anti-B7 MoAb B7–24 synergistically blocked allogeneic B cell-induced T-cell proliferation, IL-2 production, and CTL generation. These data suggest that the mere blockage of B7-CD28 interaction during allotransplantation will be insufficient to prevent rejection or graft-versus-host disease. However, low CsA concentrations, when combined with an agent blocking B7-CD28 interaction, can potentially achieve complete immunosuppression.

Detection of self-reactive CD8+T cells with an anergic phenotype in healthy individuals

Science ◽  
2014 ◽  
Vol 346 (6216) ◽  
pp. 1536-1540 ◽  
Author(s):  
Yuka Maeda ◽  
Hiroyoshi Nishikawa ◽  
Daisuke Sugiyama ◽  
Danbee Ha ◽  
Masahide Hamaguchi ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Immunological Tolerance ◽  
Healthy Individuals ◽  
Activated T Cells ◽  
Cognate Antigen ◽  
Anergic T Cells ◽  
Antigen Presenting

Immunological tolerance to self requires naturally occurring regulatory T (Treg) cells. Yet how they stably control autoimmune T cells remains obscure. Here, we show that Tregcells can render self-reactive human CD8+T cells anergic (i.e., hypoproliferative and cytokine hypoproducing upon antigen restimulation) in vitro, likely by controlling the costimulatory function of antigen-presenting cells. Anergic T cells were naïve in phenotype, lower than activated T cells in T cell receptor affinity for cognate antigen, and expressed several coinhibitory molecules, including cytotoxic T lymphocyte–associated antigen-4 (CTLA-4). Using these criteria, we detected in healthy individuals anergic T cells reactive with a skin antigen targeted in the autoimmune disease vitiligo. Collectively, our results suggest that Tregcell–mediated induction of anergy in autoimmune T cells is important for maintaining self-tolerance.

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