The homeostasis of naive, effector, and memory T lymphocytes is regulated by cytokines, MHC/peptide ligands, and apoptotic pathways. Proteins belonging to the Bcl-2 family are the major players of the intrinsic apoptotic pathway. Recent studies on the role of the Bcl-2 family in T cell apoptosis suggest that members of this family are the principal regulators of the survival/death pathways that decide the fate of T cells. However, most of the studies have focused on pro-apoptotic BH3-only and multi-domain members, leaving the roles of the anti-apoptotic members (Bcl-2, Bcl-xL, Mcl-1, and A1) in regulating the survival of naive, effector, and memory T lymphocytes largely unknown. This is partly due to a lack of appropriate in vivo animal models. For example, mice lacking Bcl-xL and Mcl-1 die embryonically. Mice lacking Bcl-2 die within 3 weeks of birth, precluding the use of these animals to examine T cell immune response in the context of pathogenic infections. We have generated mice conditionally lacking Bcl-x, Bcl-2, and Mcl-1 in T lymphocytes. In addition, we have also generated mice in which Bcl-2 expression is genetically marked. These animal models enable us to address the roles of these anti-apoptotic molecules in regulating the survival of naive, effector, and memory T lymphocytes in vivo using Listeria monocytogenes infection model. Our overall hypothesis is that Bcl-2 and Mcl-1 differentially regulate T cell survival. We propose that on one hand, Bcl-2 primarily promotes the survival of memory T cells, while Mcl-1 is required for the survival of activated/effector T cells. On the other hand, we propose that both Bcl-2 and Mcl-1 promote naive T cell survival, but through distinct mechanisms. To test the above hypothesis, we propose three specific aims: 1: To examine the role of Bcl-2 and Mcl-1 in memory T lymphocyte development. 2: To elucidate the mechanisms by which Mcl-1 protects activated T cells from death. 3: To establish the mechanisms by which Bcl-2 and Mcl-1 protect naive T cells from death. Results from our proposed research will not only establish the roles of these important anti-apoptotic proteins in T cell survival, but also provide novel insights into boosting effector and memory T cell response to microbial pathogens by enhancing their survival.

Public Health Relevance

We propose to study how T cell homeostasis is regulated by anti-apoptotic proteins. The results from this study, if funded, will provide information important in designing vaccines to boost immune response to microbial pathogens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Leitner, Wolfgang W
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Duke University
Schools of Medicine
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