Regulation of thymocyte differentiation: pre-TCR signals and beta-selection

The specificity of the adaptive immune response is, in part, dependent on the clonal expression of the mature T cell receptor (TCR) on T lymphocytes. One mechanism regulating the clonality of the TCR occurs at the level of TCR-beta gene rearrangements during lymphocyte development. Expression of a nascent TCR-beta chain together with pre-Talpha (pTalpha) and CD3 molecules to form the pre-TCR complex, represents a critical checkpoint in T cell differentiation known as beta-selection. Indeed, failure to generate a functionally rearranged TCR-beta chain at this stage of development results in apoptosis. Signals derived from the pre-TCR complex trigger a maturation program within developing thymocytes that includes: rescue from apoptosis; inhibition of further DNA recombination at the TCR-beta gene locus (allowing for the clonality of antigen receptor expression; allelic exclusion); and induction of proliferation and differentiation. The signaling mechanisms that control this developmental program remain largely undefined. Here, we discuss recent evidence investigating the molecular mechanisms that regulate thymocyte differentiation downstream of pre-TCR formation.