Functional TCR analysis of SIV specific CTL

Tulane University Of Louisiana, New Orleans LA

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Abstract

DESCRIPTION (provided by applicant): Although affinity maturation is a well-documented characteristic of B cell responses, recent studies indicate that T cells may also undergo an affinity maturation process. It is well accepted that antigen-specific T cells generated during primary immune responses are usually broadly polyclonal. However, repeated re-exposure to the same antigen gives rise to T cell populations with a more restricted T cell receptor (TCR) repertoire and higher antigen affinities. TCR repertoires of virus-specific CTL have been extensively studied in the setting of HIV-1 infection. However, the functional TCR repertoire of CD8 + T cell responses specific for individual viral epitopes remains poorly characterized in infected, and especially in vaccinated individuals. To date, studies of the TCR repertoire of epitope-specific CTL using either the entire CD8 v T cell population or tetramer technology to isolate antigen-specific CTL from PBL of infected individuals has been restricted to analysis of the alpha or beta chain separately. These studies have provided limited information concerning the functional evolution of epitope-specific CD8 + T cells. In the studies described in this application, we will use novel soluble TCR tetramers to characterize the functional evolution of TCRs that recognize dominant and subdominant SIV-, CTL epitopes that arise during immunization. Specifically, we will 1. Determine the repertoire of the TCR alpha and beta chain pairs of SIV-specific CTL generated by DNA or recombinant adenovirus vaccination of Mamu-A*01+ rhesus monkeys 2. Compare the affinities of TCR that recognize SIV CTL epitopes using soluble TCR tetramer complexes 3. Assess the affinity maturation of the TCRs involved in SIV-specific T cell responses in a heterologous prime-boost vaccination strategy.