Type I interferon inflames the helper T cell response.

摘要

Vaccine development is a major focus in the fight against human infectious diseases. Successful vaccines rely on the appropriate activation of T and B cells to form memory cells. Helper T cells are required for both killer T cell and antibody responses to infection and vaccination. Clonal expansion and effector differentiation are two critical features of the helper T cell response; a detailed understanding of which would aid rational vaccine development.;Classically, two signals from antigen presenting cells are needed for T cell activation: signal 1, the cognate peptide - MHC complex, and signal 2, costimulatory molecules. In these studies we show that type I interferon (IFNI) is a required signal 3 for optimal CD4 T cell responses (Chapter III). We compared WT and type I interferon receptor deficient (IFN-IR°) T cell receptor transgenic CD4 T cell responses against lymphocytic choriomeningitis virus in a wild type host. Loss of IFN-I receptor signaling does not lessen proliferation, but severely limits the survival of clonally proliferating cells, thus reducing overall expansion.;However, specific pathogen-host interactions seem to dictate which pro-inflammatory cytokines are used as the signal 3 for CD4 T cell expansion. For example, IFN-IR expression on CD4 T cells exhibited little impact on CD4 T cell expansion after infection with Listeria monocytogenes (Chapter IV), but direct IFN-I signals to CD4 T cells do cooperate with IL-12 for maximal IFN-gamma production. In addition, we find that CD4 T cells lacking the IFN-IR can efficiently expand in response to LCMV infection in mice in which all cells lack IFN-IR expression (Chapter V). We go on to show that IFN-IR° CD4 T cell expansion depends on the ability of bone marrow cells to receive IFN-I signals. Together, these results show a novel requirement for CD4 T cell expansion, a direct inflammatory signal 3, and suggests that the signal 3 needed for CD4 T cell expansion are flexible and determined by both the host and the pathogen.