The Vbeta8.2T cell receptor positive subset is over-represented in the encephalitogenic Lewis rat T cell repertoire. Thus, in the myelin basic protein induced autoimmune disease EAE, we have found that greater than 90% of proliferating lymph node T cells are Vbeta8.2+ while only approximately 5% of normal Lewis lymph node T cells display this phenotype. Sequencing of the TcR beta chain from autoreactive T cells specific for the encephalitogenic determinant of MBP, residues 68-88, has revealed a paucity of non-template-directed nucleotide additions in these cells, a phenotype that has been associated with """"""""fetal type"""""""" cells, such as Lyl B cells and certain gammadelta T cells. This suggests that autoreactive T cells may also be derived during early ontogeny. A second finding, that an EAE- linked beta chain was found in the neonatal spleen, supports this notion. The goal of this proposal is to determine if Vbeta8.2+ T cells share other characteristics of """"""""fetal type"""""""" cells. For example, many gamma delta T cells appear to escape thymic selection by early migration to the periphery. We will ask if the autoimmune T cells also escape negative selection by early ontogenic appearance and migration to peripheral lymphoid organs, where they can mature extrathymically. Thus, the overall aims of this proposal are: 1) to determine the ontogenic appearance and organ distribution of Vbeta8.2+ TcR RNA in Lewis rats, 2) to determine if Vbeta8.2+ T cells are present in the periphery of athymic nude Lewis rats, and 3) to examine the appearance of Vbeta8.2 with the same junctional region as that used by the adult rat MBP-specific TcR beta chain. The identification of the maturational pathways of Vbeta8.2+ T cells will increase our understanding of the origins of autoreactive T cells, and of possible mechanisms of escape from negative selection in the thymus, and could also provide insight into potential positive selection mechanisms for these autoreactive Vbeta8.2+ T cells. In this regard, we will be examining the developmental appearance of myelin basic protein and a related gene- product, Golli-MBP. Furthermore, we will be determining the effect of these molecules on T cell activation and anergy-induction.
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