T lymphocytes are generated through a combined process of intrathymic positive and negative selection that selects T cells with low but significant affinity to self peptides bound to major histocompatibility complex (MHC) molecules. Most T cells thus recognize self ligands with low affinity, but remain in a quiescent state under normal conditions. However, when the total size of the T cell pool falls below a certain level, T cells undergo considerable proliferation without intentional antigen injection. Based on studies with one line of TCR transgenic mice, it has long been believed that this """"""""homeostatic"""""""" T cell expansion is stimulated by exogenous environmental antigens and pathogens. In marked contrast with this view, we have recently found evidence that homeostatic T cell proliferation is driven by MHC molecules loaded with specific self peptides, in fact with the self peptides that initially induced positive selection of the T cells in the thymus. To fiirther extend our preliminary studies, four areas of investigation are proposed. First, information on why homeostatic proliferation does not apply to all T cells will be investigated. Second, the mechanisms involved in downregulation of the homeostatic proliferative response under normal conditions will be studied by determining the role bystander T cells play in inhibiting homeostatic responses. Third, we will analyze whether homeostatic T cell proliferation could be under the control of costimulatory or adhesion molecules. Fourth, in light of the recent finding that mature T cells disappear rapidly when deprived of contact with self MHC molecules, we will test whether survival of mature T cells also requires continuous contact with the MHC-bound self peptides that initially induce positive selection of the T cells in the thymus. Increased knowledge in this area is crucial for finding new approaches that can enhance or prolong immunity in old age.
| 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 |
| 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 |
| Sprent, Jonathan; Surh, Charles D (2009) Re-entry of mature T cells to the thymus: an epiphenomenon? Immunol Cell Biol 87:46-9 |
| 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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