Role of nuclear orphan receptors during thymocyte differentiation

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T cells, a type of white blood cells, patrol the organism to detect the presence of infectious agent. Antigenic fragments coming from infectious agent are presented to T cells in association with self-molecules of the major histocompatibility complex (MHC), by specialized cells of the immune system. The recognition of foreign substances (or antigens) by T cells via their T cell receptor (TCR), induces a variety of responses that will permit the elimination of the pathogen. Thus, T cells are crucial to fight life-threatening microbes. Each T cell expresses a distinct TCR that will be able to recognize a particular infectious agent. These different TCRs are generated by random juxtaposition of the different gene segments coding for the TCR in the genome. This process can generate up to 10e15 different TCRs. Since TCRs are produced in a random fashion and since they will have to be able to recognize foreign substances in association with self-molecules; the specificity of the TCR expressed by a T cell needs to be tested to make sure that: 1) it is not reactive against self-substances expressed by our own cells to avoid their destruction; 2) it will eventually be able to recognize a foreign substances in association with our self-MHC molecules; and 3) it has been correctly produced during the random events of its generation. This is tested during T cell development in the thymus. A better understanding of the mechanism by which T cells expressing an appropriate TCR are generated is pivotal to understand how T cells successfully eliminate foreign substances without generating autoimmunity (self-attack). Thus the goal of our proposal is to better understand how T cells expressing self-reactive TCRs are eliminated during their development in the thymus. All developmental processes and cellular responses to change in the environment are controlled by complex signaling cascades. The work described in this grant application will specifically evaluate the contribution of the molecule NR4A3 and the mechanism by which it contributes to the elimination of self-reactive T cells during thymic T cell development.