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.
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.
|Chen, Cai-Feng; Feng, Xia; Liao, Hui-Yu et al. (2014) Regulation of T cell proliferation by JMJD6 and PDGF-BB during chronic hepatitis B infection. Sci Rep 4:6359|
|Dunkle, Alexis; Dzhagalov, Ivan; Gordy, Claire et al. (2013) Transfer of CD8+ T cell memory using Bcl-2 as a marker. J Immunol 190:940-7|
|He, Ming-Xiao; He, You-Wen (2013) CFLAR/c-FLIPL: a star in the autophagy, apoptosis and necroptosis alliance. Autophagy 9:791-3|
|Dunkle, Alexis; He, You-Wen (2011) Apoptosis and autophagy in the regulation of T lymphocyte function. Immunol Res 49:70-86|
|Jia, Wei; Pua, Heather H; Li, Qi-Jing et al. (2011) Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes. J Immunol 186:1564-74|
|Gordy, Laura E; Bezbradica, Jelena S; Flyak, Andrew I et al. (2011) IL-15 regulates homeostasis and terminal maturation of NKT cells. J Immunol 187:6335-45|
|McLeod, Ian X; Zhou, Xiang; Li, Qi-Jing et al. (2011) The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Rýý surface expression. J Immunol 187:5051-61|
|Dunkle, A; Dzhagalov, I; He, Y-W (2010) Mcl-1 promotes survival of thymocytes by inhibition of Bak in a pathway separate from Bcl-2. Cell Death Differ 17:994-1002|
|Gordy, Claire; Dzhagalov, Ivan; He, You-Wen (2009) Regulation of CD8(+) T cell functions by RARgamma. Semin Immunol 21:2-7|