TCRb CDR3 and Susceptibility to Autoimmune Disease

University Of Alabama At Birmingham, Birmingham AL

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Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The capacity of the immune system to properly distinguish self from non-self depends on the ability of lymphocytes to generate a diverse repertoire of antigen-binding receptors. The mechanisms that diversify the antigen receptor repertoire and subsequently constrain the range of that diversity are of fundamental interest to the study of autoimmunity, since it is presumed that autoimmune diseases result, at least in part, from dysregulation or disruption of the proper function of these mechanisms. Although much has been done to elucidate the mechanisms that augment repertoire diversity, little is known of the mechanisms that restrict it or the potential consequences of violating these restrictions. We propose to test the hypothesis that the reason for the conservation of TCR Dbeta sequence from trout to human is that negatively charged or hydrophobic TCR beta CDR3 domains are more likely to generate self-reactive T cells that will promote or "trigger" autoimmune disease in susceptible individuals. In order to test this hypothesis, we propose the following specific aims: 1) To create a mouse with a single Dbeta locus that has been altered to promote production of negatively charged or hydrophobic TCR beta CDR3 intervals; 2) To determine the effects of altered TCR Dbeta sequence on CDR3 hydropathicity and sequence composition, and on -r cell development in the thymus and in the periphery; 3) To examine the effect of alterations in TCR Dbeta sequence on the ability of the host to respond to antigen, and 4) To begin to determine if alteration of TCR -beta sequence will promote the development of autoimmune disease. We submit that the present proposal has the potential to help us elucidate novel mechanisms that act to constrain the development of the TCR repertoire. These experiments will also shed light on the role of potentially abnormal TCR sequence in promoting lupus and other autoimmune diseases. [unreadable] [unreadable] [unreadable]