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

Nature Immunology volume 16, pages 397–405 (2015)Cite this article

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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.

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Figure 1: Expression and function of IL-7R in pre- and post-β-selection thymocytes.
Figure 2: Human Bcl-2 fails to compensate for loss of IL-7 signaling during β-selection.
Figure 3: Transcriptional response to IL-7 in DN3a, DN3b and DN4 thymocytes.
Figure 4: IL-7 signaling promotes the growth and proliferation of DN4 cells in vivo.
Figure 5: IL-7 signaling delays the differentiation of DN3b and DN4 cells into DP thymocytes.
Figure 6: Deletion of Bcl6 improves the self-renewal of DN4 cells in the absence of IL-7.
Figure 7: Il7r−/− DN4 thymocytes are not the precursors of the ISP cell subset.
Figure 8: IL-7 signaling prevents premature recombination of the Tcra locus in the DN4 subset.

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Acknowledgements

We thank R. Gerstein (University of Massachusetts) for Il7−/− mice; and R. Dalla-Favera (Columbia University) for Bcl6+/− mice. Microarray analyses were performed at The Centre for Applied Genomics, Hospital for Sick Children with support from Genome Canada/Ontario Genomics Institute and the Canada Foundation for Innovation; flow cytometry was performed at The SickKids-UHN Flow Cytometry Facility, supported by the Ontario Institute for Cancer Research, the McEwen Centre for Regenerative Medicine, the Canada Foundation for Innovation and the SickKids Foundation. Supported by the Canadian Institutes of Health Research (FRN 11530 to C.J.G.), the US National Institutes of Health (R37 GM41052 to M.S.K.), the National Center for Research Resources of the US National Institutes of Health (P41 GM103504 to G.D.B.).

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Authors and Affiliations

  1. Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Canada

    Amine Boudil, Irina R Matei, Goce Bogdanoski, Julie S Yuan, Stephen G Chang, Bertrand Montpellier, Paul E Kowalski & Cynthia J Guidos

  2. Department of Immunology, University of Toronto, Toronto, Canada

    Amine Boudil, Bertrand Montpellier & Cynthia J Guidos

  3. Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA

    Han-Yu Shih & Michael S Krangel

  4. The Donnelly Centre, University of Toronto, Toronto, Canada

    Veronique Voisin, Shaheena Bashir & Gary D Bader

  5. Department of Molecular Genetics, University of Toronto, Toronto, Canada

    Gary D Bader

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Contributions

A.B., I.R.M., H.-Y.S., G.B., J.S.Y., S.G.C., B.M. and P.E.K. designed, performed and analyzed experiments; V.V., S.B. and G.D.B. performed statistical analysis and gene set–enrichment analysis of Illumina gene-expression data; A.B., H.-Y.S. and M.S.K. wrote the manuscript; and C.J.G. analyzed data, supervised the study and wrote the manuscript.

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Correspondence to Cynthia J Guidos.

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Integrated supplementary information

Supplementary Figure 1 Gating strategy for identifying DN thymocyte subsets.

(a) Thymocytes from WT-, Il7r-/- and Il7r-/- BCL2 mice were analyzed by flow cytometry with antibodies specific for the indicated markers. To identify DN subsets we first excluded cells expressing lineage markers, CD4, CD8, and CD3 and then used differential expression of CD25, CD44 to identify the 4 DN subsets. Two-parameter contour plots (5% probability, including outliers) show sequential gates applied after first excluding dead cells, debris and doublets. First row: R1 gate on CD4 vs CD25 displays was used to exclude CD4+ cells (which would include DP and CD4 SP cells). Second row: CD8 vs CD25 displays gated on R1 were used to exclude CD8 SP cells based on R2 gate. Third row: Lin vs CD25 displays gated on R2 were used to exclude CD25- Lin+ cells using R3 gate. Fourth row: CD3 vs CD25 displays gated on R3 were used to exclude CD3+ CD25- cells using R4 gate. (b) Representative plots showing CD25 vs icTCRβ expression by DN Lin- CD3- thymocytes (sequential R1-R4 gating as shown in a). Quadrants show gates used to identify DN3a (CD25+ icTCRβ-), DN3b (CD25+ icTCRβ+) and DN4 (CD25- icTCRβ+) thymocytes. c) Representative plots showing CD25 vs CD44 expression by DN Lin- CD3- thymocytes. Quadrants show gates used to identify DN2 (CD25+ CD44+), DN3 (CD25+ CD44-) and DN4 (CD25- CD44-) thymocytes. Similar results were obtained in 3 independent experiments (a, b, c).

Supplementary Figure 2 Effect of IL-7 on global gene expression in DN3a, DN3b and DN4 thymocytes.

(a) Bar graph shows the number of genes significantly altered by IL-7 (FDR q<0.05) in each subset. (b) Cytoscape visualization of metabolism, signaling, and cell growth sub-networks that were significantly enriched in DN3a cells (nominal P < 0.01, as indicated in Supplementary Table 1). Gene-sets are depicted as circles (nodes), with connecting lines (or edges) indicating overlap between nodes. Node size is proportional to gene-set size, and edge thickness represents the degree of overlap. Nodes were colored according to enrichment results: red indicates up-regulation by IL-7. Color intensity is proportional to enrichment significance. (c) Bar graphs depict IL-7-induced fold-change (FC) in normalized expression values for genes encoding transporters and translation regulators. Data are from the Illumina gene expression profiling shown in Fig. 3. FC and FDR values are indicated in Supplementary Table 2. ND: not detected.

Supplementary Figure 3 Effect of IL-7 on DN3b and DN4 differentiation in vitro.

(a) Histograms show CD25 expression levels on Il7+/+ (shaded histograms) vs Il7-/- (open histograms) DN and ISP cells present 15h after culturing DN3b thymocytes in media or with 10 ng/ml IL-7. Data are from the experiment shown in Fig. 5a. (b) Data from the experiment shown in Fig. 5a (DN3b) and Fig. 5b (DN4) were re-plotted to show impact of IL-7 signaling on differentiation. Bar graphs show the % (mean +/- SD) of DN (icTCRβ+ CD4- CD8-), ISP (icTCRβ+ CD4- CD8+) and DP (icTCRβ+ CD4+ CD8+) cells present 15h after culturing Il7+/+ or Il7-/- cells with media (white) vs 10 ng/ml IL-7 (black, 3(Il7+/+) or 4 (Il7-/-) technical replicates/group). Statistical significance was assessed as described for Fig. 1: *P≤0.001, **P<0.05. Similar results were obtained in 3 independent experiments (a,b). Med, Media.

Supplementary Figure 4 Characterization of ISP thymocytes from Il7r–/– mice.

(a) Contour plots show representative CD24 vs CD3 distribution gated on Lin- CD4- CD8+ icTCRβ+ thymocytes from Il7r+/+ and Il7r-/- mice, ISP cells were identified as CD24+ CD3-. (b) Histograms show FSC, CD71 and CD98 expression by ISP cells from Il7r+/+ (shaded histograms) versus Il7r-/- mice (open histograms). (c) Histograms show CD71 and CD98 expression levels on eDP (Top) and lDP (Bottom) cells from Il7r+/+ (shaded) vs Il7r-/- mice (open). Similar results were obtained in at least 3 independent experiments (a, b, c).

Supplementary Figure 5 Model depicting the DN3-DN4-ISP-DP differentiation sequence in the presence and absence of IL-7 signaling.

(a) In WT mice, lDP cells are predominantly generated via the canonical linear DN3-DN4-ISP-eDP sequence. All intermediates in this sequence are Rag2-/lo, CD71hi CD98hi and highly cycling (orange rectangle), and Tcra rearrangement occurs primarily in lDP cells. (b) In Il7-/- or Il7r-/- mutant mice, cycling Rag2- CD71hi CD98hi DN3b cells differentiate into lDP cells via a branched non-canonical sequence (orange rectangle). In the quiescent pathway (blue rectangle), DN3a cells generate non-cycling Bcl6hi Rag2hi CD71- CD98lo DN4 cells that differentiate directly into lDP. Tcra rearrangement initiates prematurely in quiescent DN4 thymocytes. In the cycling pathway, CD71hi CD98hi DN3b cells generate cycling CD25+ CD71hi CD98hi ISP without going through a DN4 intermediate, and transit into cycling CD25+ CD71hi CD98hi DP before differentiating into lDP cells. During this sequence, Tcra rearrangement occurs primarily in lDP cells. Symbols in brown and green represent CD71 and CD98, respectively.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 610 kb)

Supplementary Table 1: Functional sub-groups of IL7 targets in DN3a cells.

Gene set enrichment analysis results showing gene sets that were significantly enriched in DN3a cells (nominal P < 0.01), grouped according to functions in metabolism, signaling, and cell growth. Number of genes (size), enrichment score (ES), normalized ES (NES) and nominal P-value are indicated for each gene set (XLS 34 kb)

Supplementary Table 2: Transcriptional response to IL7 in DN3a, DN3b and DN4 thymocytes.

IL-7-induced fold-change (FC) in normalized expression values for function-based groups of genes were indicated. FC with FDR q ≥ 0.05 are shown as not significant (NS) (XLS 42 kb)

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Boudil, A., Matei, I., Shih, HY. et al. IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte β-selection. Nat Immunol 16, 397–405 (2015). https://doi.org/10.1038/ni.3122

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