The mature T cell pool is regulated by extrinsic homeostatic factors to remain at a constant overall size and to be comprised of predictable proportions of naive and memory subsets of T cells. Recent investigations have revealed that the essential homeostatic factors are derived from contact with self-MHC/peptide ligands and the cytokines IL-7 and IL-15. Thus, naive T cells require TCR signals from interaction with self-MHC ligands and IL-7 for survival and to undergo homeostatic proliferation in response to severe T cell depletion. Memory CD8 cells do not require contact with MHC, but are dependent on IL-7 and IL-15 for their homeostasis. IL-7 is thought to be largely responsible for survival, whereas IL-15 is required for homeostatic proliferation. The exact homeostasis requirement for memory CD4 cells is more controversial, but recent work suggests that contact with either MHC or IL-7 is crucial. One major hindrance is the scarcity of a physiologically relevant system of generating antigen-specific memory CD4 cells. To extend our current understanding of T cell homeostasis, the following three areas of investigation are proposed. First, we will test the idea that foreign antigens enhance homeostasis of naive T cells through the activation of the innate immunity. Second, a population of physiologically relevant antigen-specific memory CD4 cells will be used to precisely define the homeostatic requirements for these cells and also the spontaneously generated memory-phenotype CD4 cells. Third, we will define the nature of competition among naive and memory subsets of T cells for homeostatic factors. The findings from these studies are likely to have important implications for the design of vaccines and therapies for treatment of immunodeficiencies and cancer.
| Cho, Jae-Ho; Kim, Hee-Ok; Surh, Charles D et al. (2010) T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity 32:214-26 |
| Sprent, Jonathan; Surh, Charles D (2009) Re-entry of mature T cells to the thymus: an epiphenomenon? Immunol Cell Biol 87:46-9 |
| van Leeuwen, Ester M M; Sprent, Jonathan; Surh, Charles D (2009) Generation and maintenance of memory CD4(+) T Cells. Curr Opin Immunol 21:167-72 |
| Boyman, Onur; Ramsey, Chris; Kim, David M et al. (2008) IL-7/anti-IL-7 mAb complexes restore T cell development and induce homeostatic T Cell expansion without lymphopenia. J Immunol 180:7265-75 |
| Ramsey, Chris; Rubinstein, Mark P; Kim, David M et al. (2008) The lymphopenic environment of CD132 (common gamma-chain)-deficient hosts elicits rapid homeostatic proliferation of naive T cells via IL-15. J Immunol 180:5320-6 |
| Purton, Jared F; Sprent, Jonathan; Surh, Charles D (2007) Staying alive--naive CD4(+) T cell homeostasis. Eur J Immunol 37:2367-9 |
| Purton, Jared F; Tan, Joyce T; Rubinstein, Mark P et al. (2007) Antiviral CD4+ memory T cells are IL-15 dependent. J Exp Med 204:951-61 |
| Rubinstein, Mark P; Kovar, Marek; Purton, Jared F et al. (2006) Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci U S A 103:9166-71 |
| Boyman, Onur; Cho, Jae-Ho; Tan, Joyce T et al. (2006) A major histocompatibility complex class I-dependent subset of memory phenotype CD8+ cells. J Exp Med 203:1817-25 |
| Surh, Charles D; Boyman, Onur; Purton, Jared F et al. (2006) Homeostasis of memory T cells. Immunol Rev 211:154-63 |
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