The role of CD154 in organ transplant rejection and acceptance

CD154 plays a critical role in determining the outcome of a transplanted organ. This simple statement is amply supported by experimental evidence demonstrating that anti–CD154 antibodies are potent inhibitors of allograft rejection in many rigorous transplant models. Unfortunately, despite intensive investigation over the past ten years, the precise mechanisms by which antibodies against CD154 exert their anti–rejection effects have remained less obvious. Though originally classified with reference to B–cell function, CD154–CD40 interactions have also been shown to be important in T cell–antigen–presenting cell interactions. Accordingly, CD154 has been classified as a T–cell co–stimulatory molecule. However, mounting data suggest that treatment with anti–CD154 antibodies does not simply block costimulatory signals, but rather that the antibodies appear to induce signalling in receptor–bearing T cells. Other data suggest that anti–CD154 effects may be mediated by endothelial cells and possibly even platelets. In fact, the current literature suggests that CD154 can either stimulate or attenuate an immune response, depending upon the model system under study. CD154 has secured a fundamental place in transplant biology and general immunology that will no doubt be the source of considerable investigation and therapeutic manipulation in the coming decade.

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IMMUNOLOGICAL TOLERANCE IN BONE MARROW-DERIVED LYMPHOCYTES

Journal of Experimental Medicine ◽

10.1084/jem.139.6.1464 ◽

1974 ◽

Vol 139 (6) ◽

pp. 1464-1472 ◽

Cited By ~ 26

Author(s):

David H. Katz ◽

Toshiyuki Hamaoka ◽

Baruj Benacerraf

Keyword(s):

T Cell ◽

B Cells ◽

Cell Function ◽

Critical Role ◽

Tolerance Induction ◽

Immunological Tolerance ◽

Antigenic Determinants ◽

Humoral Responses

The present studies were designed to probe the role(s) of T cells in preventing or altering tolerance induction in hapten-specific B cells. This was accomplished by using hapten conjugates of normally immunogenic heterologous carriers to selectively inhibit 2,4-dinitrophenyl (DNP)-primed B cells in adoptive transfer experiments in vivo. The data provide strong indications that one critical role of T-cell participation in humoral responses to antigens is to circumvent the development of a tolerogenic signal that, in the absence of such T-cell function, might otherwise ensue after binding of the antigenic determinants by specific precursor B lymphocytes.

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Impairment of Antigen-Presenting Cell Function in Mice Lacking Expression of Ox40 Ligand

Journal of Experimental Medicine ◽

10.1084/jem.191.2.365 ◽

2000 ◽

Vol 191 (2) ◽

pp. 365-374 ◽

Cited By ~ 219

Author(s):

Kazuko Murata ◽

Naoto Ishii ◽

Hiroshi Takano ◽

Shigeto Miura ◽

Lishomwa C. Ndhlovu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Critical Role ◽

Costimulatory Molecule ◽

Activated T Cells ◽

Antigen Presenting

OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L, is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L monoclonal antibody, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-immunoglobulin (Ig)M stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice engendered apparent suppression of the recall reaction of T cells primed with both protein antigens and alloantigens and a significant reduction in keyhole limpet hemocyanin–specific IgG production. The impaired T cell priming was also accompanied by a concomitant reduction of both T helper type 1 (Th1) and Th2 cytokines. Furthermore, antigen-presenting cells (APCs) derived from the mutant mice revealed an impaired intrinsic APC function, demonstrating the importance of OX40L in both the priming and effector phases of T cell activation. Collectively, these results provide convincing evidence that OX40L, expressed on APCs, plays a critical role in antigen-specific T cell responses in vivo.

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Fluctuations in TCR and pMHC interactions regulate T cell activation

10.1101/2021.02.09.430441 ◽

2021 ◽

Author(s):

Joseph R. Egan ◽

Tim Elliott ◽

Ben D. MacArthur

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Information Theoretic ◽

Histocompatibility Complex ◽

Copy Numbers ◽

Stochastic Fluctuations ◽

Antigen Presenting

ABSTRACTAdaptive immune responses depend on interactions between T cell receptors (TCRs) and peptide major-histocompatibility complex (pMHC) ligands located on the surface of T cells and antigen presenting cells (APCs) respectively. As TCRs and pMHCs are often only present at low copy numbers their interactions are inherently stochastic, yet the role of stochastic fluctuations on T cell function is unclear. Here we introduce a minimal stochastic model of T cell activation that accounts for serial TCR-pMHC engagement, reversible TCR conformational change and TCR clustering. Analysis of this model indicates that it is not the strength of binding between the T cell and the APC cell per se that elicits an immune response, but rather the information imparted to the T cell from the encounter, as assessed by the entropy rate of the TCR-pMHC binding dynamics. This view provides an information-theoretic interpretation of T cell activation that explains a range of experimental observations. Based on this analysis we propose that effective T cell therapeutics may be enhanced by optimizing the inherent stochasticity of TCR-pMHC binding dynamics.

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Peptide-induced proliferation and lymphokine production in human T cells in the absence of antigen-presenting cells: Role of T-cell activation state and costimulatory signals

Human Immunology ◽

10.1016/0198-8859(92)90110-9 ◽

1992 ◽

Vol 34 (3) ◽

pp. 173-180 ◽

Cited By ~ 7

Author(s):

Esteban Celis ◽

Joseph J. Goodwin ◽

Toshiji Saibara

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Antigen Presenting Cells ◽

Lymphokine Production ◽

Human T Cells ◽

Costimulatory Signals ◽

Antigen Presenting

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Faculty Opinions recommendation of Critical role of B cells in the development of T cell tolerance to aeroallergens.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1006737.84610 ◽

2002 ◽

Author(s):

Randolph Noelle

Keyword(s):

T Cell ◽

B Cells ◽

Critical Role ◽

T Cell Tolerance ◽

Cell Tolerance

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CERI, CEFX, and CPI: Largely Improved Positive Controls for Testing Antigen-Specific T Cell Function in PBMC Compared to CEF

Cells ◽

10.3390/cells10020248 ◽

2021 ◽

Vol 10 (2) ◽

pp. 248

Author(s):

Alexander A. Lehmann ◽

Pedro A. Reche ◽

Ting Zhang ◽

Maneewan Suwansaard ◽

Paul V. Lehmann

Keyword(s):

T Cell ◽

Mononuclear Cells ◽

Cell Function ◽

Racial Bias ◽

Immune Monitoring ◽

Functional Fitness ◽

Peripheral Blood Mononuclear ◽

Cell Immunity ◽

Antigen Presenting ◽

Positive Controls

Monitoring antigen-specific T cell immunity relies on functional tests that require T cells and antigen presenting cells to be uncompromised. Drawing of blood, its storage and shipment from the clinical site to the test laboratory, and the subsequent isolation, cryopreservation and thawing of peripheral blood mononuclear cells (PBMCs) before the actual test is performed can introduce numerous variables that may jeopardize the results. Therefore, no T cell test is valid without assessing the functional fitness of the PBMC being utilized. This can only be accomplished through the inclusion of positive controls that actually evaluate the performance of the antigen-specific T cell and antigen presenting cell (APC) compartments. For Caucasians, CEF peptides have been commonly used to this extent. Moreover, CEF peptides only measure CD8 cell functionality. We introduce here universal CD8+ T cell positive controls without any racial bias, as well as positive controls for the CD4+ T cell and APC compartments. In summary, we offer new tools and strategies for the assessment of PBMC functional fitness required for reliable T cell immune monitoring.

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CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

Journal of Experimental Medicine ◽

10.1084/jem.20081811 ◽

2009 ◽

Vol 206 (2) ◽

pp. 421-434 ◽

Cited By ~ 160

Author(s):

Randall H. Friedline ◽

David S. Brown ◽

Hai Nguyen ◽

Hardy Kornfeld ◽

JinHee Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cell Function ◽

Cytotoxic T Lymphocyte ◽

Critical Role ◽

Lymphoproliferative Disease ◽

In Trans ◽

And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

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