Premature TCR alpha beta 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. TCR alpha b eta transgenic (Tg) mice have no such delay, consequently expressing rearra nged TCR alpha beta proteins early in the ontogeny. Such mice exhibit reduc ed thymic cellularity and accumulate mature, nonprecursor TCR(+)CD8(-)4(-) thymocytes, believed to be caused by premature Tg TCR alpha beta expression via unknown mechanism(s). Here, we show that premature expression of TCR a lpha beta on early thymocytes curtails thymocyte expansion and impairs the CD8(-)4(-) --> CD8(+)4(+) transition. This effect is accomplished by two di stinct mechanisms. First, the early formation of TCR alpha beta appears to impair the formation and function of pre-TCR, consistent with recently publ ished results, Second, the premature TCR alpha beta contact with intrathymi c MHC molecules further pronounces the block in proliferation and different iation. These results suggest that the benefit of asynchronous Tcr-a and Tc r-b rearrangement is not only to minimize waste during thymopoiesis, hut al so to simultaneously allow proper expression/function of the pre-TCR and to shield CD8(-)4(-) thymocytes from TCR alpha beta signals that impair thymo cyte proliferation and CD8(-)4(-) --> CD8(+)4(+) transition.