The overall goal of this project is to test the hypothesis that the intestine is an extrathymic site of T extrathymic T cell maturation. If extrathymic sites of T cell production exist, then thymic involution may not adversely affect the immune system at that site. Moreover, an extrathymic site of T cell generation could partially supplant thymic T cell production. In addition, the potential for autoreactivity may be greater if T cell receptor (Tcr) selection mechanisms in extrathymic sites are not as stringent as those of the thymus, as has been suggested for selection of extrathymic IEL. Thus, the major concern of this project is to determine the T cell generative potential of the small intestine using murine model systems. Our preliminary results indicate that the thymus plays an integral role in the production and/or maturation of IEL expressing either the gammadelta or alpha beta Tcr. The results are consistent with IEL precursors maturing directly in the thymus but also leave open the possibility that the thymus has a """"""""remote site"""""""" influence on IEL maturation in the intestine. Thus, our aims are centered around determining which of these scenarios is correct or whether elements of both are involved.
The specific aims are;
AIM 1. TO DETERMINE WHETHER THE INFLUENCE OF THE THYMUS ON IEL MATURATION IS DIRECT OR INDIRECT.
The aim will determine whether IEL are derived directly from the thymus or are indirectly influenced by the presence of the thymus using neonatal thymectomy (nTX) and thymus grafting experiments;
AIM 2. TO DETERMINE IEL PRECURSOR MATURATION POTENTIAL AT DIFFERENT DEVELOPMENTAL STAGES.
This aim will determine at what developmental stage the thymus, or other precursor sources such as fetal liver, are necessary for IEL production./ AIM 3. TO DETERMINE THE ROLE OF THE THYMUS IN IEL TCR SELECTION.
This Aim will test whether iEL Tcr selection occurs under the influence of the thymus or directly in the intestine. beta2-microglobulin-deficient mice and gammadelta Tcr transgenic mice will be used to determine the site of alpha beta and gammadelta IEL Tcr selection. Overall, this project will provide significant insight into the T cell generative potential of the intestine and the developmental biology of the intestinal immune system.
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