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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI057753-01A2
Application #
6983776
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Nabavi, Nasrin N
Project Start
2005-06-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$367,600
Indirect Cost
Name
Children's Hospital Med Ctr (Cincinnati)
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Raynor, Jana; Lages, Celine S; Shehata, Hesham et al. (2012) Homeostasis and function of regulatory T cells in aging. Curr Opin Immunol 24:482-7

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