Interaction with bone marrow derived cells is required for early t cell development in the thymus

During intrathymic T cell differentiation, immature thymocytes maturate to CD4*8 or CD4 8* stage when their TcR recognizes self MHC molecules. Although the thymus provides a unique environment for this event, it is unknown whether positive selection is mediated by all thymic epithelial cells (TEC) or by some specialized subsets. To address this issue, we generated two strains of mice transgenic for both 2B4 TcRctβ and HLADRa genes; DRa-24/2B4 TcRaβ transgenic mice (Tg) expressing DRoEβ molecule on TEC and bone marrow derived cells (BDC) and DRa-30/2B4 TcRaβ Tg expressing DRaEβ molecule on only TEC. In an analysis for thymocyte development in these mice, we found that CD4'8+ (DP) thymocytes could maturate to CD4*8 stage only in the DRa24/2B4 TcRaβ Tg. This indicates that positive selection of T cells requires the interaction of their TcR with relevant MHC molecules on BDC in TcR Tg. To confirm this, H-2 class I and II double knock-out DRa-24 mouse (Ebra) and DRa-30 mouse (Edun) were generated. Inconsistent with the observation in TcR Tg, DP thymocytes could maturate to CD4+8- stage not only in Ebra but also in Edun, indicating that MHC molecules on BDC does not contribute to the maturation of immature thymocytes in physiological condition. Recent studies have shown the possibility that pTa-TcRβ complex regulates early T cell development in the thymus. Because interaction of 2B4 TcRaβ with DRoEβ on BDC was essential for the development of immature thymocytes in TcRaβ Tg and because maturation to CD4+8 stage was observed in Edun, it is suggested that interaction of TcRaβ with relevant MHC on BDC can mimic the interaction of pTa-TcRβ with its natural ligand and that this ligand is a non-MHC molecule expressed on BDC.