Premature TCRαβ expression and signaling in early thymocytes impair thymocyte expansion and partially block their development

In thymocyte ontogeny, Tcr-a genes rearrange after Tcr-b genes. TCRαβ transgenic (Tg) mice have no such delay, consequently expressing rearranged TCRαβ proteins early in the ontogeny. Such mice exhibit reduced thymic cellularity and accumulate mature, nonprecursor TCR⁺CD8^-4^- thymocytes, believed to be caused by premature Tg TCRαβ expression via unknown mechanism(s). Here, we show that premature expression of TCRαβ on early thymocytes curtails thymocyte expansion and impairs the CD8^-4 → CD8⁺4⁺ transition. This effect is accomplished by two distinct mechanisms. First, the early formation of TCRαβ appears to impair the formation and function of pre-TCR, consistent with recently published results. Second, the premature TCRαβ contact with intrathymic MHC molecules further pronounces the block in proliferation and differentiation. These results suggest that the benefit of asynchronous Tcr-a and Tcr-b rearrangement is not only to minimize waste during thymopoiesis, but also to simultaneously allow proper expression/function of the pre-TCR and to shield CD8^-4^- thymocytes from TCRαβ signals that impair thymocyte proliferation and CD8^-4^- → CD8⁺4⁺ transition.