T Cell Homeostasis in the Alloimmune Response

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): The vast majority of activated/effector T cells generated during the proliferative phase of the immune response undergo apoptosis. The few T cells that avoid death, or somehow are prevented from dying, return to a relatively quiescent state and persist as antigen-specific memory T cells. The factors that allow some activated or effector T cells to survive and progress to the memory phase are not well understood. We propose here to investigate these factors using an allogeneic transplantation model in which the fate of activated, effector, or memory T cells can be studies in the absence of confounding primary immune responses. The central hypothesis of this grant application is that the transition of activated T cells to memory is an instructional process, which requires the presence of cytokines that inhibit activated T cell proliferation and apoptosis. We propose that the allograft influences this transition process. The specific aims are: 1. To investigate whether cytokines that inhibit T cell proliferation allow activated T cells to avoid apoptosis and transition to memory. Specifically, we will focus on the tumor growth factor-beta (TGF13) and type-1 interferon (IFN-1) cytokine families. We will test whether the allograft contributes to the transition of activated T cells to memory by producing (TGF13) or IFN-1. 2. To investigate whether the anatomic location of an allograft influences the transition of activated/effector T cells to memory. Specifically, we will examine whether transplanting a graft into an immunologically privileged site results in a smaller memory pool due to the exaggerated apoptosis of activated and memory T cells. 3. To investigate whether antagonizing the cytokines that prevent activated T cell death facilitates the induction of tolerance by enhancing the deletion of antigen-specific T cells. An allospecific CD8 T cell receptortransgenic (TCR-tg) adoptive transfer model will be used to address the specific aims of this grant application. The proposed studies will therefore focus on CD8 T cell homeostasis in the alloimmune response.