Cell Biology and Genetics of T Cell Activation and Death A network of cytoplasmic proteins, originally described to mediate cell death, can assemble in different combinations and at different cellular locations to regulate several aspects of immunity. In response to 'Death Receptor'(DR) ligation a complex of Fadd, Tradd, Ripk1, and Caspase-8 assemble to form the 'Death inducing signaling complex'(Disc) that causes apoptotic cell death. In the absence of Caspase-8 activity, these same molecules along with Ripk3 can assemble to carry out a separate 'necroptotic'form of cell death. We propose that the absence of Caspase-8 is a molecular signature of viral infection, e. g., herpes family or pox family viruses, and as a counter defense, vertebrates have evolved a parallel pathway of cell death. Three fundamental concepts in immunology are addressed in this application. 1) How does Caspase-8 regulation of innate immunity in dendritic cells affect the magnitude and quality of the adaptive immune response? 2) How do different pathways of virally-induced cell death affect the course of disease, clearance of virus, and the differentiation of T cells? 3) What are the death pathways operative in the contraction of T cells and the resolution of an immune response following viral infection, how do these principles differ between persistent and acute viral infections? The approaches include a step-wise analysis of the innate and adaptive immune responses to viral infections in mice with selective mutations in the genes encoding Disc components. Understanding the biology underlying T cell expansion and cell death is important in designing new immunologically-based therapeutic strategies, especially for infectious agents mediating persistent viral infections.
One of the most important mechanisms of medical intervention relies on vaccination against infectious disease, yet for many persistent viral infections, an effective vaccine is not at hand. In particular, the evasion strategies of viruses often affect cellular suicide mechanisms necessary for an effective and well-regulated immune response. This proposal explores manner in which three different modes of cell death control the immune response to strategically selected viral infections.
|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|
|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|
|Günther, 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; 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|
|Catlett, Ian M; Hedrick, Stephen M (2005) Suppressor of cytokine signaling 1 is required for the differentiation of CD4+ T cells. Nat Immunol 6:715-21|
|Beisner, Daniel R; Ch'en, Irene L; Kolla, Ravi V et al. (2005) Cutting edge: innate immunity conferred by B cells is regulated by caspase-8. J Immunol 175:3469-73|
|Beisner, Daniel R; Chu, Isaac H; Arechiga, Adrian F et al. (2003) The requirements for Fas-associated death domain signaling in mature T cell activation and survival. J Immunol 171:247-56|
|Onami, Thandi M; Lin, Meei-Yun; Page, Dawne M et al. (2002) Generation of mice deficient for macrophage galactose- and N-acetylgalactosamine-specific lectin: limited role in lymphoid and erythroid homeostasis and evidence for multiple lectins. Mol Cell Biol 22:5173-81|
|Page, D M; Roberts, E M; Peschon, J J et al. (1998) TNF receptor-deficient mice reveal striking differences between several models of thymocyte negative selection. J Immunol 160:120-33|
Showing the most recent 10 out of 11 publications