STAT5 and the Regulation of CD8+ T Cell Differentiation

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DESCRIPTION (provided by applicant): The broad objective of this research is to understand the signaling mechanisms that determine T cell fate after encounter with antigen. To effectively mount an immune response to pathogens and tumors, T cells must differentiate into effector cells capable of eliminating these targets. However, in some instances the immune system may become tolerant to a specific antigen to avoid autoimmunity. Therefore, the balance between tolerance and immune activation is critical for normal health. We are interested in identifying the signals that determine CD8+ T cell tolerance versus differentiation into cytotoxic T lymphocytes (CTL), and how the context of antigen encounter may regulate this decision The cytokines IL-2 and IL-15 promote CTL differentiation, and the transcription factor STAT5, which these cytokines activate, regulates expression of CTL effector molecules. Therefore, activation of STAT5 in CD8+ T cells is expected to promote important aspects of the CTL phenotype. We hypothesize that the context in which the CD8+ T cell encounters antigen determines the T cell response, and that STAT5 may regulate this cell fate decision. Our specific aims are: (1) to determine if CD8+ T cells, when activated in vivo either under inflammatory versus non-inflammatory or under tolerizing versus immunizing conditions, proliferate in two distinct modes that are distinguished by the utilization of STAT5, and (2) to determine if STAT5 activation is associated with and required for the expression of cytolytic effector genes and specific cytolytic activity by CD8+ T cells stimulated in vivo.