In the last 4 years of funding we have defined the conditions under which T cells obviate the requirement forcostimulatory signaling during activation, and mediate graft rejection in murine models of transplantationdespite treatment with reagents that profoundly Inhibit costimulatory T cells to T cells. Specifically, ourresearch 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 ofcostlmulatlon blockade. These findings have been based on the use of TCR transgenic models which allowthe use of a fixed, monoclonal T cell population in order to control for the effects of altered TCR affinity forantigen, among other variables present In endogenous, polyclonal, polyantigen-speclfic populations.However, during the course of our studies we have begun to Investigate the role of TCR affinity for pMHCcomplexes during graft rejection, and how this parameter fundamentally impacts the magnitude andcharacter ofthe donor-reactive T cell response during graft rejection or survival. After establishing a noveltransgenic system In which graft specific T cells are primed by ligands of increasing affinity for the TCR, wehave demonstrated In preliminary studies that graft-specific TCR affinity profoundly impacts the effectorphenotype of responding T cells, and more Importantly, critically influences their suscepfibility tocosfimulatlon blockade- Induced prolongafion in graft survival. Therefore, experiments outlined In thisproposal will endeavor to elucidate the role of TCR affinity in preclpltafing graft rejection, and to assess themechanisms underlying the ability of cells stimulated with ligands of varying potencies to be tolerized usingcostlmulatlon blockade. These studies are of great significance because they will allow us to begin to unravelthe nature of the alloreactive T cell response, and define a threshold for TCR cross-reactivity above whichclinical manifestations of T cell alio- crossreactlvity will occur.
The proposed research is relevant to public health because fissue and organ transplantafion is a life-savingtreatment opfion for many end-stage organ diseases; however, combating the potent Immune response thatthreatens to destroy transplanted fissue remains an important problem. This grant applicafion seeks tounderstand 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 advancingfundamental 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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