Early events regulating post-viral immunopathology

Dartmouth College, Hanover NH

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Abstract

? DESCRIPTION (provided by applicant): The controlled contraction of immune responses during the clearance of respiratory virus infection is critical to resolution of inflammation and te limitation of lung injury. The kinetics of antiviral effector CD8+ T cell contraction, and dampenin of effector function, appears to be programmed during the initial activation of naive T cells, and possibly prior. Among other negative regulators of immune responses, it has long been appreciated that TNF-alpha signaling plays an important role in contraction of CD8+ effector T cells, though the precise mechanisms involved remain unclear. We've shown that the critical timing of TNF-programmed contraction occurs within the first 24-48 hours after initial antigen recognition, and plays little immunoregulatory role thereafter. Furthermore, the critical source of this early burst of TNF production is the naive CD8+ T cell upon initial antigen recognition. We hypothesize that the ability of the naive CD8+ T cell to produce an early TNF burst is critically dependent upon homeostatic type I interferon signaling in the host milieu prior to infection. The IFN-mediated regulation of the early burst of TNF-? by naive CD8+ T cells is quite complex, and appears dependent upon post-thymic peripheral T cell licensing, during which the impact of constitutive low-level IFN production confers the tendency to mount this important early TNF response. We propose that this involves epigenetic licensing of naive T cells for this critical activity. The fundamental hypothesis of this proposal is that signals from the host milieu impinge upon naive CD8+ T cell through epigenetic events, which have a direct impact on the kinetics of the contraction of the T cell responses and effector activities during and after viral infection, serving to limit lung injury and immunopathology.