IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte β-selection.
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.
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.
Amine
A
Boudil
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Canada.
Irina R
IR
Matei
Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
Han-Yu
HY
Shih
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Canada.
Goce
G
Bogdanoski
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Canada.
Julie S
JS
Yuan
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Canada.
Stephen G
SG
Chang
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.
Bertrand
B
Montpellier
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Canada.
Paul E
PE
Kowalski
The Donnelly Centre, University of Toronto, Toronto, Canada.
Veronique
V
Voisin
The Donnelly Centre, University of Toronto, Toronto, Canada.
Shaheena
S
Bashir
1] The Donnelly Centre, University of Toronto, Toronto, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Gary D
0000000301858861
GD
Bader
Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
Michael S
MS
Krangel
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.
Cynthia J
0000000276742612
CJ
Guidos
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D005786:Gene Expression Regulation; D015851:Interleukin-7 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051881:Receptor, Notch1 / Q000235:genetics* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D011995:Recombination, Genetic; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D015704:CD4 Antigens; D016827:CD8 Antigens; D015851:Interleukin-7; C497762:Notch1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta; C576410:interleukin-7, mouse; C052617:Bcl2 protein, mouse