IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte beta-selection

Signaling via the pre-T cell antigen receptor (pre-TCR) and the receptor Notch1 induces transient self-renewal (beta-selection) of TCR beta(+) CD4(-)CD8(-) double-negative stage 3 (DN3) and DN4 progenitor cells that differentiate into CD4(+)CD8(+) double-positive (DP) thymocytes, which then rearrange the locus encoding the TCR alpha-chain (Tcra). Interleukin 7 (IL-7) promotes the survival of TCR beta(-) DN thymocytes by inducing expression of the pro-survival molecule BcI-2, but the functions of IL-7 during beta-selection have remained unclear. Here we found that IL-7 signaled TCR beta(+) DN3 and DN4 thymocytes to upregulate genes encoding molecules involved in cell growth and repressed the gene encoding the transcriptional repressor BcI-6. Accordingly, IL-7-deficient DN4 cells lacked trophic receptors and did not proliferate but rearranged Tcra prematurely and differentiated rapidly. Deletion of BcI6 partially restored the self-renewal of DN4 cells in the absence of IL-7, but overexpression of BCL2 did not. Thus, IL-7 critically acts cooperatively with signaling via the pre-TCR and Notchl to coordinate proliferation, differentiation and Tcra recombination during beta-selection.