"Basis for selection of MHC-independent alpha-beta T Cells in the thymus"
The thymus generates MHC-restricted abT cells that only recognize antigenic ligands in association with MHC or MHC-like molecules. We have recently reported that MHC-independent abT cells can be generated in mice deficient in both coreceptors as well as MHC, called ‘Quad-deficient' mice, and that such mice contained a diverse abT cell repertoire whose MHC-independence was confirmed at the clonal level. We now show that signaling and selection of these MHC-independent T cells required the presence of TCR as Quad-/- thymocytes deficient in TCRa and pTa expression were not signaled nor selected. Furthermore, we were able to confer the MHC-independent specificity of individual T cell hybridomas by retrovirally introducing both TCRa and TCRb chains in a TCR negative cell line. The critical effect of the Lck sequestration by coreceptors was examined by introducing CD4 transgenes into Quad-deficient mice. Whereas sequestration of Lck by wild-type CD4 blocked signaling by non-MHC ligands on ab thymocytes, introducing a tailless form of CD4 didn't. Finally, we generated Lck transgenes that cannot interact with CD4 and CD8 coreceptors and we were able to generate MHC independent abT cells. We conclude that in the absence of Lck sequestration by coreceptors, thymocytes can be signaled by non-MHC ligands. Collectively these data demonstrate that CD4 and CD8 coreceptors impose MHC-specificity on a broad abTCR repertoire by preventing thymocytes to be selected by non-MHC ligands.