ROLE OF TYPE-I IFN'S IN ANTIVIRAL CD8 CELL RESPONSE

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The long-term objectives of our research are to understand the mechanisms by which acute viral infections induce potent immune responses with a hope that the knowledge gained from infectious models can be applied for improving vaccination strategies. Our previous studies, using mouse models of lymphocytic choriomeningitis virus (LCMV) infection, demonstrated that acute viral infections induce a much higher magnitude of primary and memory CD8 T cell responses than was previously thought. We found that these anti-viral memory CD8 cells persist for extended periods even in the absence of T cell receptor-MHC class I interactions. Now it is becoming clear that some infections can elicit significant T cell responses even in the absence of costimulatory molecules or professional APC help. The underlying mechanisms are not clear. To better understand these mechanisms, we started characterizing possible events that may contribute to the enhanced T cell response in viral infection. We found that infection-induced type-I interferons (IFNodl3)(a) helps potentiate the CD8 T cell response and (b) cause a transient activation of na'fve T cells early after infection. We hypothesize that this IFNcdl3 mediated sensitization of na'fve CD8 T cells may provide an additional signal that potentiates the ability to respond to antigen. As a result, the na'fve CD8 T cells may respond well even in the absence of co-stimulatory and or professional APC help under the conditions of infection. This proposal is aimed at testing this by pursuing the following hypotheses: (1) that naive CD8 T cells, upon sensitization by infection-induced IFNcdl3 may lower their activation threshold and respond better to cognate antigenic stimulus, (2) that IFNcz/13receptorpositive (IFNRc_/13+/+)CD8 T cells may have a selective advantage over receptor negative (IFNRcdl3-/-) CD8 T cells in eliciting immune response during viral infection, and, (3) that IFNRcdl3+/+ CD8 T cells may become less dependent upon professional APC help than IFNRcdI3-/- CD8 T cells during an anti-viral response. These studies will provide insight into the biological consequences of bystander T cell activation in viral infections and the mechanisms of cross-talk between innate and adaptive immunity. This work has implications for improving vaccination strategies and provides groundwork for future studies aimed at understanding the mechanisms involved in generation of immune memory and have significance for human and animal health.