Mechanisms and consequences of CD3 rearrangement during TCR triggering

Mayo Clinic Rochester, Rochester MN

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Abstract

DESCRIPTION (provided by applicant): There is significant interest in the development of 'T cell adjuvants', biocompounds capable of enhancing T cell immune responses against tumors or chronic infections. In order to target diseased tissue for elimination, T cells must recognize antigens via the T cell antigen receptor (TCR), and induce a conformational change in the TCR-associated CD3 complex (v). However, the mechanism(s) by which this occurs, and the precise contribution this makes to T cell immunity, are not completely understood. In this project, we propose to elucidate the protein sequences controlling CD3?c in experiments designed to inform new conceptual models regarding the structural aspects of T cell activation. We will focus on the TCR/CD3 subunits, domains, and amino acid sequences involved in CD3?c. Relevant sequences that are discovered in this manner will be mutated and expressed to ascertain their functional contribution to T cell development and activation. We will also determine the contribution that exogenous provision of CD3?c imparts to T cell function, via the use of a new reagent we have generated. This reagent can induce CD3?c without inducing other T cell signaling, and therefore it is inert to non-antigen-engaged T cells. However, the reagent appears to enhance T cell activation by weak antigens, and thus may represent a novel class of 'T cell adjuvant'. We will examine the ability of this reagent to lower the T cell activation signaling threshold, and to enhance T cell-mediated tumor rejection in mice. The information obtained from these studies will advance our comprehension of antigen recognition by T cells, and point toward CD3?c as molecular target with therapeutic potential.