In the last 4 years of funding we have defined the conditions under which T cells obviate the requirement for costimulatory signaling during activation, and mediate graft rejection in murine models of transplantation despite treatment with reagents that profoundly Inhibit costimulatory T cells to T cells. Specifically, our research has shown that the presence of high naive CD4'^ or CDS* T cell precursor frequency or pre- existence of donor-reactive memory T cells render recipients refractory to the salutary effects of costimulation blockade. These findings have been based on the use of TCR transgenic models which allow the use of a fixed, monoclonal T cell population in order to control for the effects of altered TCR affinity for antigen, among other variables present In endogenous, polyclonal, polyantigen-specific populations. However, during the course of our studies we have begun to Investigate the role of TCR affinity for pMHC complexes during graft rejection, and how this parameter fundamentally impacts the magnitude and character of the donor-reactive T cell response during graft rejection or survival. After establishing a novel transgenic system In which graft specific T cells are primed by ligands of increasing affinity for the TCR, we have demonstrated In preliminary studies that graft-specific TCR affinity profoundly impacts the effector phenotype of responding T cells, and more Importantly, critically influences their susceptibility to costimulatlon blockade- Induced prolongation in graft survival. Therefore, experiments outlined In this proposal will endeavor to elucidate the role of TCR affinity in precipitating graft rejection, and to assess the mechanisms underlying the ability of cells stimulated with ligands of varying potencies to be tolerized using costlmulatlon blockade. These studies are of great significance because they will allow us to begin to unravel the nature of the alloreactive T cell response, and define a threshold for TCR cross-reactivity above which clinical manifestations of T cell alio- crossreactlvity will occur.
The proposed research is relevant to public health because tissue and organ transplantation is a life-saving treatment option for many end-stage organ diseases;however, combating the potent Immune response that threatens to destroy transplanted tissue remains an important problem. This grant application seeks to understand the factors that allow T cells to mount a vigorous Immune attack against the transplanted tissue. Therefore, the proposed research is relevant to the part of NIH's mission that relates to advancing fundamental knowledge in order to help reduce human morbidity and mortality.
|Krummey, S M; Cheeseman, J A; Conger, J A et al. (2014) High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept. Am J Transplant 14:607-14|
|Ford, Mandy L; Stempora, Linda L; Larsen, Christian P (2011) CD28 blockade induces division-dependent downregulation of interleukin-2 receptor alpha. Transpl Immunol 24:94-9|
|Ferrer, Ivana R; Wagener, Maylene E; Song, Minqing et al. (2011) Antigen-specific induced Foxp3+ regulatory T cells are generated following CD40/CD154 blockade. Proc Natl Acad Sci U S A 108:20701-6|
|Ford, Mandy L; Larsen, Christian P (2011) Transplantation tolerance: memories that haunt us. Sci Transl Med 3:86ps22|
|Reisman, Natalie M; Floyd, Tamara L; Wagener, Maylene E et al. (2011) LFA-1 blockade induces effector and regulatory T-cell enrichment in lymph nodes and synergizes with CTLA-4Ig to inhibit effector function. Blood 118:5851-61|
|Araki, Koichi; Gangappa, Shivaprakash; Dillehay, Dirck L et al. (2010) Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation. J Exp Med 207:2355-67|
|Floyd, Tamara L; Orr, Steven B; Coley, Shana M et al. (2010) High-frequency alloreactive T cells augment effector function of low-frequency CD8+ T-cell responses under CD28/CD154 blockade. Transplantation 89:1208-17|
|Ford, Mandy L; Larsen, Christian P (2010) Overcoming the memory barrier in tolerance induction: molecular mimicry and functional heterogeneity among pathogen-specific T-cell populations. Curr Opin Organ Transplant 15:405-10|
|Araki, Koichi; Turner, Alexandra P; Shaffer, Virginia Oliva et al. (2009) mTOR regulates memory CD8 T-cell differentiation. Nature 460:108-12|
|Coley, Shana M; Ford, Mandy L; Hanna, Samantha C et al. (2009) IFN-gamma dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell responses. J Immunol 182:225-33|
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