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Nat Immunol. 2015 Apr;16(4):397-405. doi: 10.1038/ni.3122. Epub 2015 Mar 2.

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

Author information

1
1] Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Canada. [2] Department of Immunology, University of Toronto, Toronto, Canada.
2
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Canada.
3
Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
4
The Donnelly Centre, University of Toronto, Toronto, Canada.
5
1] The Donnelly Centre, University of Toronto, Toronto, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Canada.

Abstract

Signaling via the pre-T cell antigen receptor (pre-TCR) and the receptor Notch1 induces transient self-renewal (β-selection) of TCRβ(+) 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 α-chain (Tcra). Interleukin 7 (IL-7) promotes the survival of TCRβ(-) DN thymocytes by inducing expression of the pro-survival molecule Bcl-2, but the functions of IL-7 during β-selection have remained unclear. Here we found that IL-7 signaled TCRβ(+) DN3 and DN4 thymocytes to upregulate genes encoding molecules involved in cell growth and repressed the gene encoding the transcriptional repressor Bcl-6. Accordingly, IL-7-deficient DN4 cells lacked trophic receptors and did not proliferate but rearranged Tcra prematurely and differentiated rapidly. Deletion of Bcl6 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 Notch1 to coordinate proliferation, differentiation and Tcra recombination during β-selection.

Comment in

PMID:
25729925
PMCID:
PMC4368453
DOI:
10.1038/ni.3122
[Indexed for MEDLINE]
Free PMC Article

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