Maintenance of T cell homeostasis is critical for normal functioning of the adaptive immune system. Although T cell homeostasis is ultimately achieved through maintenance of distinct T cell populations (naive, effector, memory), the mechanisms by which homeostasis is maintained in each population is unclear. Although IL-7 is critical for survival of T cells in vivo at each of these stages, little is known about the downstream survival mechanisms by which homeostasis of distinct T cell populations are controlled. Our preliminary data indicate that the anti-apoptotic molecule, Bim and its anti-apoptotic antagonist, Bcl-2, regulate T cell homeostasis, at least in part by altering T cell survival in distinct populations. Bcl-2 is critical for naive T cell survival, at least in part, to counteract the pro-apoptotic effects of Bim. In viral-specific effector T cells, levels of IL-7Ralpha and Bcl-2 are decreased on most viral-specific T cells, leaving them susceptible to the pro-apoptotic effects of Bim. In the absence of Bim the numbers of a particular type of viral-specific memory T cell are increased, both functionally and phenotypically. These data suggest that the role of Bim is to limit the numbers of effector T cells that can enter the memory compartment. However, not all memory T cells are affected and the long-term survival of memory T cells may not require Bim or Bcl-2. Taken together, these data suggest that the maintenance of independent populations of T cells within the host is controlled by their different dependence on apoptosis/survival molecules. The central hypothesis of this proposal is that progression from naive to memory T compartments Involves stage-specific dependence on a dynamic balance between Bim and Bcl-2, a balance that affects IL-7-dependent survival of naive, effector, and effector memory but not central memory T cells.
The aims of the project are to determine the roles of Bim and Bcl-2 in : 1. naive T cell homeostasis; 2. effector T cell apoptosis; 3. memory T cell survival and phenotype. The long-term goal of this research is to identify molecular targets that could be exploited therapeutically to enhance T cell survival (i.e. to improve vaccination) or to decrease T cell survival (i.e. suppress autoimmune disease or transplant rejection).

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - B (CMI)
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Leitner, Wolfgang W
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Cincinnati Children's Hospital Medical Center
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McNally, Jonathan P; Millen, Scott H; Chaturvedi, Vandana et al. (2017) Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases. Proc Natl Acad Sci U S A 114:E4782-E4791
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