Immature Thymocytes Employ Distinct Signaling Pathways for Allelic Exclusion versus Differentiation and Expansion

AbstractT cell receptor (TCR) β chain allelic exclusion occurs at the thymocyte CD4−8− (double-negative, or DN) to CD4+8+ (double-positive, or DP) transition, concurrently with differentiation and cellular expansion, and is imposed by a negative feedback loop in which a product of the first rearranged TCRβ allele arrests further recombination in the TCRβ locus. All of the major events associated with the development of DP cells can be induced by the introduction of TCRβ or activated Lck transgenes. Here, we present evidence that the signaling pathways that promote thymocyte differentiation and expansion of RAG-deficient DN cells but not those that suppress rearrangements of endogenous TCRβ genes in normal DN cells are engaged by activated Ras. We propose that TCRβ allelic exclusion is mediated by effector pathways downstream of Lck but independent of Ras