Cell Biology and Genetics of T Cell Activation and Death At the initiation of viral or bacterial infection antigen-specific T cells are programmed to proliferate and accumulate to very large numbers. The magnitude of proliferation sums the rates of cell division and cell death, and it is dependent on the persistence of antigen, growth factors, nutrients, and stress. This T cell expansion plays an important role in the clearance of infectious agents, but with characteristic kinetics, the population undergoes an equally dramatic decline to a small steady-state population of memory T cells. Experiments are proposed to test the hypothesis that T cells have co-evolved with natural pathogens to avoid virulence mechanisms aimed at the inhibition of cell death. Select caspases (cysteine proteases) mediate several aspects of cellular suicide leading to apoptosis, and yet inhibition of Caspase-8, a form of viral evasion, results in an alternate program of cell death. We have now determined that Ripk1 is a sensor of caspase-8 activity, and mediates an alternate form of cell death in the absence of Caspase-8. Experiments are proposed to characterize the different forms of cell death occurring at various phases of the immune response with or without a Caspase-8 deletion. The approaches include genetic complementation with genes known to regulate apoptosis, necrosis and autophagy, and morphological analyses using transmission electron microscopy and confocal immunofluorescence. Understanding the biology underlying T cell expansion and cell death is important in designing new immunologically-based therapeutic strategies, especially for infectious agents mediating chronic diseases. PROJECT NARRATIVE: One of the most important mechanisms of medical intervention relies on vaccination against infectious disease, yet many diseases are resistant to our standard vaccine strategies. In particular, the evasion strategies of infectious agents often include the inhibition of cellular suicide mechanisms necessary for an effective and well-regulated immune response. This proposal explores the biology and genetics of cell death in the immune system with a particular emphasis in understanding how apoptosis, necrosis, and autophagy contribute to T cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037988-15
Application #
7910727
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Leitner, Wolfgang W
Project Start
1995-06-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
15
Fiscal Year
2010
Total Cost
$382,388
Indirect Cost
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Delpoux, Arnaud; Michelini, Rodrigo Hess; Verma, Shilpi et al. (2018) Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8+ T cells. J Exp Med 215:575-594
Tsau, Jennifer S; Huang, Xin; Lai, Chen-Yen et al. (2018) The Effects of Dendritic Cell Hypersensitivity on Persistent Viral Infection. J Immunol 200:1335-1346
Lee, Sang-Yun; Coffey, Francis; Fahl, Shawn P et al. (2014) Noncanonical mode of ERK action controls alternative ?? and ?? T cell lineage fates. Immunity 41:934-46
Mingueneau, Michael; Krishnaswamy, Smita; Spitzer, Matthew H et al. (2014) Single-cell mass cytometry of TCR signaling: amplification of small initial differences results in low ERK activation in NOD mice. Proc Natl Acad Sci U S A 111:16466-71
Cuda, Carla M; Misharin, Alexander V; Gierut, Angelica K et al. (2014) Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. J Immunol 192:5548-60
G√ľnther, Claudia; Martini, Eva; Wittkopf, Nadine et al. (2011) Caspase-8 regulates TNF-?-induced epithelial necroptosis and terminal ileitis. Nature 477:335-9
Ch'en, Irene L; Tsau, Jennifer S; Molkentin, Jeffery D et al. (2011) Mechanisms of necroptosis in T cells. J Exp Med 208:633-41
Hedrick, Stephen M; Ch'en, Irene L; Alves, Bryce N (2010) Intertwined pathways of programmed cell death in immunity. Immunol Rev 236:41-53
Ch'en, Irene L; Beisner, Daniel R; Degterev, Alexei et al. (2008) Antigen-mediated T cell expansion regulated by parallel pathways of death. Proc Natl Acad Sci U S A 105:17463-8
D'Souza, Warren N; Hedrick, Stephen M (2006) Cutting edge: latecomer CD8 T cells are imprinted with a unique differentiation program. J Immunol 177:777-81

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