REGULATION OF T CELL HOMEOSTASIS AND SURVIVAL

Scripps Research Institute, La Jolla CA

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Abstract

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.