T Cell Repertoires Specific for Defined Viral Epitopes

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Immunity to a number of infectious pathogens is known to be mediated by CD8+ T cells, implying that many vaccines should be engineered to elicit strong CD8+ T cell memory. Recent experiments from our laboratory and others have shown that antigen-specific CD8+ T cell memory populations are heterogeneous at two levels. At one level, they express a matrix of cell surface markers that evolves continuously, even in the absence of antigen. At a second level, populations of antigen-specific CD8+ T cells contain a surprisingly diverse variety of T cell receptor clonotypes, but the repertoire of these clonotypes does not continue to evolve in the absence of persisting or exogenous antigen. CD62L, the lymph node homing receptor, is a marker expressed on naive T cells, lost on antigen-specific cells early during the acute immune response, and slowly regained on an increasing fraction of memory cells as a function of time. In Specific Aim I of this proposal, we will examine 1) the origin of antigen-specific CD8+ memory T cells that are clearly distinguished by their levels of expression of CD62L, the lymph node homing receptor, and 2) the immunological role of these distinct populations during secondary immune responses. The existence of clear CD62L+ and CD62L memory T cell subsets in the mouse is reminiscent of the central and effector T cell memory populations in humans recently described by Lanzavecchia and colleagues, and our studies will provide a rigorous test of this emerging paradigm. In Specific Aim II, we will explore the hypothesis that memory T cell subsets are heterogeneous with respect to their homing properties, expression of molecules intimately involved in cytolytic effector function, and in verifiable lytic function, and that these subsets perform distinct immunological functions. For these studies, we will develop necessary new reagents and assays, including the following: 1) a panel of "chemokine tetramers" for the determination of chemokine receptor expression at the single cell level; 2) antibodies or ligands specific for mouse perforin and granzyme B; and 3) a truly single-cell CTL assay capable of detecting lytic function of antigen-specific cells present at low frequency. Finally, in Specific Aim III, we propose to investigate the hypothesis that T cell receptor repertoires specific for epitopes present in a latent persistent virus will continue to evolve and become less diverse over time as a result of latent gene expression or periodic reactivation of a lytic viral program. These studies will directly compare the evolution of mouse CD8+ T cell repertoires specific for epitopes in gamma HV-68 to the repertoires induced by non-persisting vectors containing the same epitopes.