Although mast cells are best known for their role in the pro-inflammatory processes that mediate allergic responses, recent data from several laboratories including ours have implicated mast cells as critical players in a variety of other pathologic and protective immune responses. For example, mast cells are required for maximal disease in murine models of multiple sclerosis (Experimental allergic encephalomyelitis - EAE) and arthritis and for resistance to many bacterial infections. In EAE, mast cells exert their effects on both CD4+ and CD8+ autoreactive T cell responses. T cells derived from immunized mast cell-deficient mice (W/Wv) exhibit reduced antigen-specific IFN?, IL-17 production, attenuated alterations in activation markers including CD44, CD11a, CD69 and CD62L as well as an inability to efficiently traffic to the target tissues in the CNS when compared with cells isolated from their wild type littermates. In this setting, the sub-optimal CD8+ T cell response was most striking and may be due to inefficient mast cell-dependent CD4+ T cell help. It may reflect a more direct influence of mast cells on CD8+ T cells. Alternatively, mast cells may indirectly alter T cell responses through effects on dendritic cell function and migration. Experiments in this application will utilize mast cell-deficient mice to test the hypothesis that mast cells contribute to a microenvironment that shapes events governing primary and memory CD4+ and CD8+ T cell function using a well characterized infection model that elicits robust CD4+ and CD8+ T cell responses to lymphocytic choriomeningitis (LCMV) virus epitopes that are necessary for long-term protective immunity to this virus. Understanding all of the factors that lead to a strong memory response is essential for effective vaccine development.
The specific aims are: 1) To define the roles of mast cells in LCMV-specific CD4+ and CD8+ T responses. 2) To examine the influence of mast cells on dendritic cell maturation, migration and T cell stimulatory function in LCMV-infected mice. ? ?
