Research: This is a research proposal to examine the role of apoptosis in the development of T cell memory. Upon infection, T cells undergo rapid clonal expansion resulting in both increased numbers and higher frequency of antigen specific T cells. An initial expansion phase is quickly followed by a contraction phase (clonal contraction) where more than 90% of the antigen specific T cells are eliminated. The surviving antigen specific T cells create the memory pool and provide durable protection from re-challenge. The studies proposed herein are designed to elucidate the mechanisms by which apoptosis specifically shapes the quality and function of the developing antigen specific T cell memory pool. In particular, our aims are to: 1) Determine the role of death receptor mediated apoptosis pathways in the generation and homeostasis of the memory T cellcompartment. 2) Examine the function of the Bcl-2 regulated, mitochondrial dependent apoptosis pathway in the development of the antigen specific T cell memory. 3) Examine the relationship between proliferation and susceptibility to apoptosis during antigen mediated immune responses in the generation of T cell memory. The proposed research integrates our understanding of T cell function with current ideas regarding the role of apoptosis. ^Candidate: Dr. Bensinger graduated summa cum laude from the University of Pennsylvania School of Veterinary Medicine and received his Ph.D. (2003) from University of Pennsylvania School of Medicine under the mentorship of Dr. Laurence Turka. His thesis in immunology was focused on the development and function of regulatory T cells. He is currently a research scientist at the La Jolla Instiute for Allergy and Immunology (L1AI) in the laboratory of Dr. Douglas Green. *Environment: Dr. Green is currently the head of cellular immunology at LIAI, and is recognized as an expert in both the fields of immunology and apoptosis with an outstanding publication record. He has a strong track record of training independent scientists. LIAI is an internationally recognized leader in both the fields of immunology and molecular cell biology and provides an excellent environment with the necessary in house facilities to conduct the proposed research.
| Hong, Cynthia; Kidani, Yoko; A-Gonzalez, Noelia et al. (2012) Coordinate regulation of neutrophil homeostasis by liver X receptors in mice. J Clin Invest 122:337-47 |
| Wolkers, Monika C; Bensinger, Steven J; Green, Douglas R et al. (2011) Interleukin-2 rescues helpless effector CD8+ T cells by diminishing the susceptibility to TRAIL mediated death. Immunol Lett 139:25-32 |
| Bensinger, Steven J; Tontonoz, Peter (2008) Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454:470-7 |
| Bensinger, Steven J; Bradley, Michelle N; Joseph, Sean B et al. (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134:97-111 |
