Establishment of in vitro experimental model for studying molecular mechanism of self-reactive T cell clone

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Intrathymic differentiation pathway, T cell clones are selected into TCR repertoires specific for individuals after their random generation. This process is very important for immune functions which are based on discrimination of self and non-self. Our project was addressed to determine the molecular mechanism that regulates the selection of TCR repertoires by producing a developmental model. In this study, we produced transgenic mice (Tg) for TCR which are MHC class 11 (I-Ad) restriced and OVA specific. In combination of T cells from TCR-Tg and a thymic stromal cell clone, we demonstrated that negative selection (N.S) was induced in vitro on DP cells when OVA-peptide was presented on I-Ad of both thymic and non-thymic stromal cells, indicating that stromal cells for N.S required to express selecting MHC but can be substituted by selecting MHC bearing non-thymic derived cells. For positive selection (P.S), ontogenical studies including FTOC showed that TCR expression on DP cells was not redused in thymic environment with restricting MHC but reduced in unappropriate MHC thymus. In the latter thymocytes, TCR expression was recovered by anti-CD4 treatment. Thses clearly demonstrated that the active down regulation of TCR is overcome on DP stage by TCR-mediated signaling which triggeres P.S process.