T CELL ACTIVATION AND FUNCTIONAL AVIDITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. CD8+ T cells are critical for the control and clearance of many microbial and parasitic infections, and are key to the success of many potential vaccination strategies. Despite the broad clinical relevance of T cell-mediated immunity and the intense investigation of this subject, the underlying mechanisms involved with eliciting effective T cell responses still remain to be fully determined. To begin to address this issue, we have analyzed antigen-specific T cells directly ex vivo using peptide/MHC-tetramers and functional assays that measure cytolytic activity and cytokine production. Following acute viral infection, we have found that T cell responsiveness (termed functional avidity) to peptide antigen increased significantly in both normal and T cell receptor (TcR) transgenic mice, even though TcR avidity remained virtually unaltered. Preliminary analysis of Lck expression and function indicates that pre-assembly of the TcR signal transduction machinery may serve as an important mechanism for decreasing the threshold of activation in antigen-specific CD8+ T cells. The focus of this proposal is to more thoroughly characterize the process of functional avidity maturation by dominant and subdominant CD8+ T cell populations during the course of acute viral infection, and to determine if increased antigen sensitivity is related to increased Lck expression, localization, and/or its state of activation. The results of these studies will be important for improving vaccine design as well as furthering our knowledge of antiviral T cell immunology.