Evolution of CD8+ TCR affinity during chronic viral infection

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DESCRIPTION (provided by applicant): CD8+ T cells are critical components of the adaptive immune response important for controlling viral infections. The affinity of T cell receptor for antigen triggers the activation of CD8+ T cells and drives the extent of the anti-viral response. Despite the key role of affinity in T cell activation, we still know quite little about the dynamic of antigen recognition in terms of the breadth of affinities and potential changes in affinity as the immune response evolves from initial triggering stage through memory. In addition, we lack data on differences in T cell affinities during acute infections, which elicit effective immune responses, and chronic infections where cellular immunity proves ineffective. The importance of TCR affinity for antigen recognition and our lack of knowledge are compelling reasons to investigate this issue. Toward these goals, we propose to use the micropipette adhesion assay to rigorously define the breadth of CD8+ T cell affinities in 2 dimensions (2D) during acute, chronic, and epitope loss viral infections. Recent work has highlighted the importance of 2D kinetic measurements to obtain an accurate view of T cell and APC interactions. While our proposal is focused toward the LCMV animal model to demonstrate proof of concept and define the role of affinity, the techniques could be readily transferred to patient samples to assess T cell affinity and CD8+ T cell precursor frequency during chronic infections such as HIV and HCV for which peptide antigens and HLA restriction molecules have been identified. The proposed experiments will increase our knowledge of T cell biology during chronic immune responses, with application to any situation in which T cells participate in the pathology. To test the stated hypotheses as to the breadth of the CD8+ anti-viral T cell response, we propose the following three specific aims: Aim 1- Determine the affinity profile of CD8+ T cells undergoing acute or chronic viral infections. Aim 2- Define the affinity profile and the parameters of diminished fitness of CD8+ T cells challenged by viral escape mutants. Aim 3- Characterize the affinity profile of CD8+ T cells after therapeutic interventions. PUBLIC HEALTH RELEVANCE: CD8+ T cells play a major role in the anti-viral immune response. The overall goal of this grant is to define the range of polyclonal T cell affinities for viral antigens during acute and chronic infections. The proposed studies apply a novel means for assessing affinity to the LCMV animal model, but our results should be equally translatable to human chronic infections such as HIV and HCV. Therefore, our findings are highly relevant to human health and will prove to be a valuable asset for assessing disease prognosis and for the development of effective treatments.