SELECTION OF THE T CELL RECEPTOR REPERTOIRE

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): The process of T cell differentiation in the thymus includes the rearrangement and expression of genes encoding the T cell receptor (TCR) that recognizes foreign antigens and triggers the T cell to perform its immune function. The repertoire of expressed TCRs must exclude those that recognize self-antigens, and only part of this process of tolerance induction takes place in the thymus. We have established a mouse model system for studying CD4+ T cell self-tolerance imposed outside the thymus. In these Vbeta5 transgenic animals, CD4+ T cells encounter a peripherally expressed tolerogen encoded by mouse mammary tumor virus (Mtv-) 8 and are driven along one of two tolerance pathways. The bulk of cells are deleted, a process that drives the age-dependent inversion of the CD4:CD8 ratio in the periphery. Alternatively, chronic encounter with the self-antigen can trigger CD4+ T cells to rearrange endogenous TCR genes, and express novel, nonautoreactive TCRs by a process called TCR revision. It is unclear whether this post-thymically generated TCR repertoire is self-tolerant, or whether the resulting population of CD4+ T cells can respond to antigen in vivo. The antigen recognition pattern of post revision T cells has not been explored, and it is unknown whether the apparent flexibility created by TCR revision offers a competitive advantage to cells expressing a revised repertoire in vivo. The goal of the proposed experiments is to improve our understanding of the forces that mold the revised repertoire and the potential functions of cells bearing post- thymically generated TCRs, through the following aims. Aim 1: To assess the immunocompetence and homeostasis of CD4+ T cells expressing revised TCRs. Aim 2: To determine whether the immune repertoire and self-reactivity of revised TCRs is altered when revision occurs in the absence of Fas-mediated death. Aim 3: To explore whether deletion of RAG in the periphery prevents TCR revision and results in autoimmunity and/or loss of immune flexibility. Aim 4: To engineer a line of TCR revision prone TCRalpha-beta transgenic mice, and to use laser assisted microdissection to analyze the T cell products of revision within germinal centers.