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Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus

Nature Immunology volume 18, pages 1218–1227 (2017)Cite this article

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Abstract

T cell antigen receptor (TCR) signaling in the thymus initiates positive selection, but the CD8+-lineage fate is thought to be induced by cytokines after TCR signaling has ceased, although this remains controversial and unproven. We have identified four cytokines (IL-6, IFN-γ, TSLP and TGF-β) that did not signal via the common γ-chain (γc) receptor but that, like IL-7 and IL-15, induced expression of the lineage-specifying transcription factor Runx3d and signaled the generation of CD8+ T cells. Elimination of in vivo signaling by all six of these 'lineage-specifying cytokines' during positive selection eliminated Runx3d expression and completely abolished the generation of CD8+ single-positive thymocytes. Thus, this study proves that signaling during positive selection by lineage-specifying cytokines is responsible for all CD8+-lineage-fate 'decisions' in the thymus.

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Figure 1: The induction of Runx3d by non-γc cytokine signals.
Figure 2: Non-γc cytokines generate SP8 cells during FTOC.
Figure 3: In vivo signaling by non-γc cytokines is required for the generation of γc-independent CD8+ T cells.
Figure 4: Non-γc cytokines do not generate a unique subset of CD8+ T cells.
Figure 5: TGF-β contributes to generation of γc-independent CD8+ T cells.
Figure 6: Elimination of in vivo signaling by all lineage-specifying cytokines.
Figure 7: In vivo cytokine signaling is always required for the generation of SP8 cells.

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Acknowledgements

We thank T. McCaughtry for initial contributions to the project; J.-H. Park, V. Lazarevic, D. Singer, X. Zhou and M. Kimura for critical reading of the manuscript; M. Kubo (Tokyo University of Science) for SOCSTg mice; W. Leonard (National Heart, Lung and Blood Institute) for TSLPRKO mice; W. Chen (National Institute of Dental and Craniofacial Research) for Tgfbr1fl mice; D. Littman (New York University) for Runx3dYFP mice; R. Bosselut (National Cancer Institute) for ThPOKKO mice; and S. Sharrow, A. Adams and L. Granger for flow cytometry. Supported by the Intramural Research Program of the US National Institutes of Health, the National Cancer Institute, the Center for Cancer Research and the US National Institutes of Health (R01AI097244-01A1 to T.E.).

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Authors and Affiliations

  1. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Ruth Etzensperger, Tejas Kadakia, Xuguang Tai, Amala Alag, Terry I Guinter & Alfred Singer

  2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Takeshi Egawa

  3. Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey

    Batu Erman

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  1. Ruth Etzensperger
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Contributions

R.E. designed the study, performed experiments, analyzed data and contributed to the writing of the manuscript; T.K., X.T., T.I.G. and T.E. performed experiments, analyzed data and provided helpful discussions; A.A. and B.E. generated experimental mice; and A.S. designed and supervised the study, analyzed data and wrote the manuscript.

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Correspondence to Alfred Singer.

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Integrated supplementary information

Supplementary Figure 1 Cytokine receptors on developing thymocytes that can potentially signal Runx3d expression.

(a) Characterization of γc-independent SP8 cells. Stainings for maturation markers (top) and CD8 lineage markers (bottom) are shown for B6 (black) and γccKO (red) SP8 (CD8SP TCRβhi) cells, compared to DP (CD4+ CD8+) cells (shaded curves). (b) List of cytokines, cytokine receptor chains, and signaling molecules examined in this study. (c) Identification of intermediate stage (CD4+CD8loCD69+) thymocytes that have been signaled by MHC class I-dependent ligands to undergo positive selection and to differentiate into SP8 thymocytes. MHC class I-signaled thymocytes were obtained from MHCIIKOCD1dKO mice because MHCI-signaled thymocytes in these mice do not differentiate into CD4+ NKT cells. (d) Surface expression of non-γc cytokine receptor chains on intermediate stage thymocytes from MHCIIKOCD1dKO mice. Cytokine receptor stainings are shown in red, control stainings are in gray. One of two experiments is shown. (e) Schematic of the DP stimulation assay. Pre-selection DP thymocytes (CD69-CD4+CD8+) were electronically sorted and stimulated with PMA+Ionomycin for 16h; washed and rested in medium for 10h; and then cultured with cytokines for 16-20h. Cells were then harvested and their gene expression analyzed by quantitative PCR. (f) List of cytokines that we tested in the B6 DP stimulation assay and their upregulation of mRNAs encoding Runx3d, Runx1, Runx2, Cbfb and Bcl2 (−, no gene up-regulation; +, minimal gene up-regulation; ++, intermediate gene up-regulation; +++, high gene up-regulation).

Supplementary Figure 2 Effect of cytokines on the generation of SP8 cells in fetal thymic organ culture.

(a) Thymocyte profiles of E16.5 B6 thymic lobes before and after 5 days FTOC in medium (top and middle rows). Profile of TCRβhi thymocytes on d5 of FTOC (bottom row) and numbers in boxes within the profiles indicate frequency of cells within that box. (b) SP8 cell generation in γccKO FTOCs by non-γc cytokines. Bar graph of SP8 cell frequencies from γccKO FTOCs cultured with the indicated cytokines, with SP8 cell frequencies in each cytokine group compared to medium alone (horizontal red dashed line). As an additional comparison, SP8 cell frequencies from B6 FTOCs are also shown. Data are from 4-17 individual lobes combined from 2-6 experiments. (c) IL-13 fails to induce SP8 cell generation in FTOCs. Comparison of SP8 cell frequencies (left) and numbers (right) in γccKO FTOCs cultured for 5 days with or without IL-13. SP8 cells from B6 FTOC are shown for comparison (black bar). (d) Exogenous addition of any lineage-specifying cytokine increases SP8 cell generation in B6 FTOCs. Bar graph of SP8 cell frequencies (left) and numbers (right) in B6 FTOCs cultured for 5 days with the indicated cytokines compared to medium alone cultures. Mean and s.e.m. are shown. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Supplementary Figure 3 Lymph node SP8 cells in CytoQuad mice.

Numbers of CD8 TCRβ+ LN T cells in the indicated mice. Mean and s.e.m. are shown.

Supplementary Figure 4 γc cytokines and non-γ c cytokines signal overlapping CD8+ T cell populations.

Onion diagram for schematic representation of cytokine redundancy. We think that, in normal mice, all SP8 cell generation is signaled by the γc cytokine IL-7. In the absence of IL-7 signaling, fewer SP8 cells are generated and these are signaled by the γc cytokine IL-15. In the absence of γc signaling, still fewer SP8 cells are generated and these are signaled by four non-γc cytokines (IL-6, IFN-γ, TSLP, and TGF-β). It is only in the absence of in vivo signaling by the other three non-γc cytokines (IL-6, IFN-γ, and TSLP) that the contribution of TGF-β signaling to SP8 cell generation is appreciated. Most importantly, elimination of in vivo signaling by all six of these cytokines eliminates SP8 cell generation.

Supplementary Figure 5 Analysis of STAT- and SMAD-binding sites in the Runx3d locus.

(a) Vista conservation analysis of murine and human Runx3d genomic regions. Peaks represent degree of conservation. Colored circles indicate potential binding sites for STATs (red) and SMADs (blue). (b) Comparison of surface CD103 expression on SP8 thymocytes from the indicated mice.

Supplementary Figure 6 Lineage-specifying transcription factors and the generation of SP8 cells.

(a) The Runx3dYFP/YFP DP stimulation assay (schematized in supplementary Fig. 1e) was performed with pre-selection DP thymocytes from Runx3d-deficient (Runx3dYFP/YFP) mice. After PMA+ionomycin stimulation, the Runx3dYFP/YFP DP thymocytes were stimulated with various cytokines and assessed for expression of Runx1 mRNA. (b) Generation of MHC-II specific SP8 cells in ThPOK-deficient mice requires cytokine signaling. Thymocyte profiles from the indicated mice. Numbers in boxes in the profiles indicate CD8SP cell frequencies. Mean and s.e.m. are shown.

Supplementary Figure 7 Signaling events in the thymus that generate SP8 thymocytes: all generation of SP8 cells requires signaling by lineage-specifying cytokines.

TCR signaling of DP thymocytes selectively terminates Cd8 gene expression, causing surface CD8 protein expression to decline. (a) In wildtype mice, MHC-I-specific TCR signaling eventually ceases because of the loss of surface CD8 protein expression, which allows cells to then be signaled by lineage-specifying cytokines. Signaling of positively selected thymocytes by lineage-specifying cytokines induces high Runx3d expression which both inhibits Runx1 and mediates co-receptor reversal (i.e. Cd4 gene silencing and Cd8 gene re-expression), resulting in differentiation into SP8 cells. (b) In the absence of intra-thymic signaling by lineage-specifying cytokines, Runx3d expression is not induced and Runx1 is unable to generate SP8 cells. (c) In Runx3d-deficient mice, intra-thymic signaling by lineage-specifying cytokines augments the ability of Runx1 to mediate coreceptor reversal and promote SP8 cell generation. (d) In ThPOK-deficient mice, CD4-lineage specification cannot occur. Because MHC-II-specific TCR signaling in the thymus must eventually cease, perhaps because of limiting ligand expression, cessation of TCR signaling allows the cells to then be signaled by lineage-specifying cytokines that induce high Runx3d expression which then inhibits Runx1 and mediates co-receptor reversal with the result that MHC-II-specific thymocytes differentiate into SP8 cells.

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Etzensperger, R., Kadakia, T., Tai, X. et al. Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus. Nat Immunol 18, 1218–1227 (2017). https://doi.org/10.1038/ni.3847

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