The strength and duration of immune responses are tightly regulated so as to be appropriate for a given antigenic stimulus. This regulation is due in part to the phenotype of the dendritic cells (DC) that present Ag. DC phenotype is a manifestation of maturation, activation state, and the expression of specific signaling molecules, but may also be due to factors determined by DC lineage. The relationship between distinct DC subtypes and costimulatory molecule expression and regulatory function has not been established. A defect in the regulation of T cell response is seen in mice with the Paucity of Lymph node T cells (plt) mutation. This mutation involves a deletion of genes encoding the chemokines SLC and ELC, which are known to regulate the localization of T cells and DC. Our findings suggest that a defect in the localization of a specific DC population leads to increased T cell responses in plt mice and that a relationship exists between leukocyte localization and the regulation of T cell response that has not previously been demonstrated. Based on our findings, we hypothesize that a signal provided by a distinct population of DC serves to modulate the strength and duration of immune response by regulating the activation and survival of Ag-specific T cells. This population of DC may represent either a distinct lineage or a particular differentiation state. In plt mice this population is not present, not Ag-bearing, or fails to interact with T cells. The goals of this proposal are to identify mechanisms controlling the localization of specific dendritic cell populations, to identify the defects within these populations that occur in plt mice, and to determine how these populations regulate the strength and duration of immune response.
Our specific aims are: 1.To determine the roles of SLC and ELC in controlling DC localization and immune response by developing murine models with defined genetic abnormalities. 2.To determine the cellular and functional abnormalities in DC populations that leads to increased T cell responses in mutant mice. 3.To identify the specific mechanisms by which the DC-mediated regulation of immune response is altered in mutant mice.
| Nakano, Hideki; Lin, Kaifeng Lisa; Yanagita, Manabu et al. (2009) Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses. Nat Immunol 10:394-402 |
