Cellular caspase-8 (FLICE)-like inhibitory protein (c-FLIP) is an important regulator of death receptor-induced apoptosis and plays an essential role in thymocyte maturation. Two major isoforms of c-FLIP derived from alternative mRNA splicing, c-FLIPL and c-FLIPS, have been identified in mouse T lymphocytes. Our previous studies have demonstrated that conditional deletion of both c-FLIP isoforms in T lymphocytes results in an almost complete lack of mature T cells and increased apoptosis of single positive (SP) thymocytes. To further define the roles played by the c-FLIPL and c-FLIPS isoforms in thymocyte maturation and peripheral T cell function, we have generated mice specifically lacking the c-FLIPL (c-FLIPL-/-) or c-FLIPS (c-FLIPS-/-) isoform. Surprisingly, we found that expression of c-FLIPS but not c-FLIPL in c-FLIP conditional knockout mice rescued thymocyte development. Our studies further demonstrate that c-FLIPL is essential for mature T cell proliferation, as T cells from c-FLIPL-/- mice fail to develop into effectors after Listeria monocytogenes infection. Although accumulating evidence suggests that c-FLIP has both anti-apoptotic and cell signaling functions, the mechanisms by which c-FLIP regulates thymocyte maturation and mature T cell homeostasis remain unknown. Based on our preliminary results, we hypothesize that c-FLIP has three major functions mediated through c-FLIPL and c-FLIPS in the T cell compartment: 1. c-FLIPS protects mature SP thymocytes from TCR-induced apoptosis in the thymic medulla. 2. Both c-FLIP isoforms are essential in maintaining mature T cell homeostasis by promoting survival and proliferation. 3. c-FLIPL regulates T cell proliferation through its cleaved form c-FLIPp43. In this proposal, we will test these three hypotheses using several c-FLIP genetic models we have generated. The results will not only provide important insights into the mechanisms by which c-FLIP regulates thymocyte maturation and T cell homeostasis but also provide a better understanding of general T lymphocyte biology. Furthermore, determining the role of c-FLIP in regulating effector T cell survival may improve strategies for immunization and vaccine design. ? ? Narrative: c-FLIP is an important protein that protects T lymphocytes from death and is essential for T lymphocyte to develop. Our proposed studies will provide important information on how c-FLIP protects T cells and when it will protect T cells from death. Results from this study will improve our understanding of immunodeficiency and the regulation of immune response to microbial pathogen infections. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI073947-01A1
Application #
7372851
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
Project Start
2008-03-01
Project End
2013-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
1
Fiscal Year
2008
Total Cost
$390,000
Indirect Cost
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
He, Ming-Xiao; He, You-Wen (2015) c-FLIP protects T lymphocytes from apoptosis in the intrinsic pathway. J Immunol 194:3444-51
Gordy, Claire; Liang, Jie; Pua, Heather et al. (2014) c-FLIP protects eosinophils from TNF-?-mediated cell death in vivo. PLoS One 9:e107724
He, Ming-Xiao; He, You-Wen (2013) CFLAR/c-FLIPL: a star in the autophagy, apoptosis and necroptosis alliance. Autophagy 9:791-3
He, M-X; He, Y-W (2013) A role for c-FLIP(L) in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes. Cell Death Differ 20:188-97
Piao, Xuehua; Komazawa-Sakon, Sachiko; Nishina, Takashi et al. (2012) c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. Sci Signal 5:ra93
Paul, Suman; Kashyap, Anuj K; Jia, Wei et al. (2012) Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-?B. Immunity 36:947-58
Schattenberg, Jörn M; Wörns, Marcus A; Zimmermann, Tim et al. (2012) The role of death effector domain-containing proteins in acute oxidative cell injury in hepatocytes. Free Radic Biol Med 52:1911-7
He, Ming-Xiao; He, You-Wen (2012) Suppressing autoimmunity by TGF-?: not just through T(reg) cells. Cell Mol Immunol 9:371-2
McLeod, Ian X; He, You-Wen (2012) Editorial: TRPV1: how thymocytes sense stress and respond with autophagy. J Leukoc Biol 92:409-11
McLeod, Ian X; Jia, Wei; He, You-Wen (2012) The contribution of autophagy to lymphocyte survival and homeostasis. Immunol Rev 249:195-204

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