2013-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/695502The immune system evolves several sophisticated strategies to regulate immune responses. In general, contact with the specific antigen drives naïve T cells to proliferation and differentiation. As the end of an immune response, most antigen-activated T cells die. The activated T cell death is important to maintain immune homeostasis and to prevent autoimmune diseases. Therefore, to elucidate the molecular mechanism of activated T-cell death is crucial for depicting T cell reactivity, immunological memory and autoimmunity. It is becoming clear that activated T-cell death occurs in two conditions: cytokine withdrawal and repeated antigenic stimulation. Some studies demonstrated that activated T cells die in the absence of Fas or TNFR signaling, suggesting there exists some death pathways independent of death receptors. Emerging evidence has shown that the mitochondria-centric death pathway has been implicated in the shutdown of T cell immune responses and Bcl-2 family proteins rule a crucial checkpoint of the mitochondria-mediated death pathway. Recent studies have further indicated that Bcl-2 family members play an important role in activated T cell death in vivo. However, decreased expression of Bcl-2 is not sufficient to drive the activated T cells to death, and Bak-, Bax- or Bim- deficiency can not prevent all the activated T cells from death, suggesting the involvement of other alternative mechanisms. In addition, one of the main factors hindering the success of T cell immunotherapy against cancer is premature death of tumor-reactive T cells. It has been shown that the death of tumor-reactive T cells is through mitochondrial pathway. It is intriguing to examine their role in the regulation of tumor-reactive T cell death. Blm-s (Bcl-2 like molecule, small transcript) is identified a novel member of Bcl-2 superfamily by Dr. Huang Pei-Hsin. In cooperation with Dr. Huang Pei-Hsin, we plan to study the potential role of Blm-s in regulation of mitochondria-centric death of activated T cells. Our preliminary data showed that Blm-s was upregulated in antigen-stimulated T-cells. We therefore propose that Blm-s plays a critical role in the mitochondrial-centric death pathway for both activated and tumor-reactive T cells. The aims of the study are (1) to characterize Blm-s protein in activated T cells before and after exposure to death stimuli; (2) to investigate whether Blm-s plays a key role in regulating activated T cell death in vitro and in vivo, and to elucidate whether Blm-s levels are regulated by TCR and/or CD28 costimulatory signals; (3) to study whether tumor-reactive T cell death is regulated by Blm-s protein and whether IL-2 signal at T cell priming counter-regulates the Blm-s function to render the tumor-specific T cells more resistant to death. My intent in this study is to investigate whether Blm-s plays a critical role in the mitochondrial-centric death pathway for both activated and tumor-reactive T cells. Such approaches will advance our understanding of the regulation of T-cell homeostasis. It will also be of value in taking us one step closer to optimize strategies of T cell immunotherapy for cancer.Blm-sBcl-2 familymitochondria-centric cell deathactivated T cell death