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The homeostatic γc cytokines IL-7 and IL-15 suppress the induction of CD4+CD8αα+ intraepithelial T cells in the gut

Cellular & Molecular Immunology volume 19, pages 751–753 (2022)Cite this article

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All T cells require cytokine signaling for their development and maintenance, and CD8αα+ IEL T cells are noted for their requirement for IL-15 [8]. This IL-15 dependency was demonstrated by the paucity of CD8αα+ T cells among SI IELs in Il15–/– mice (Fig. 1d and Fig. S1a). However, the cytokine requirements of CD8αα+CD4+ T cells are currently unclear. Because of the shared phenotype of CD8αα expression with CD8αα+ IELs, we postulated that CD4+CD8αα+ IELs would also depend on IL-15. Surprisingly, however, CD4+CD8αα+ IELs were still present in Il15–/– mice (Fig. 1e and Fig. S1b), and both their cell frequencies and numbers were substantially increased compared to those of littermate controls (LMCs) (Fig. 1e). CD4+CD8αα+ IEL T cell frequencies were also markedly increased in IL-15Rα-deficient mice (Fig. S1c), indicating distinct cytokine requirements for CD8αα+ and CD4+CD8αα+ IELs; specifically, IL-15 signaling is necessary for CD8αα+ IEL T cells but detrimental for CD4+CD8αα+ IEL T cells. Notably, CD4+CD8αα+ IELs displayed robust expression of IL-2Rβ and γc, the cytokine receptor subunits critical for IL-15 binding and signaling [9], indicating that these cells are IL-15-signaling competent, similar to CD8αα+ T cells (Fig. 1f). In agreement, in vitro IL-15 stimulation potently triggered downstream STAT5 phosphorylation in CD4+CD8αα+ IELs (Fig. 1g). Altogether, these results suggest that CD4+CD8αα+ T cells are IL-15 responsive but that IL-15 negatively regulates rather than promotes their differentiation.

Together with IL-15, the γc family cytokine IL-7 is a prominent homeostatic cytokine for T cells (Fig. S2a, S2b) [9]. Thus, we next investigated whether IL-7 also contributes to constrain the CD4+CD8αα+ IEL pool. To this end, we assessed the SI IEL T cell compartment of Il7–/– mice and identified a dramatic increase in CD4+CD8αα+ T cell frequency (Figs. 1h, i and Fig. S2c). The frequency of CD8αα+ IELs, however, remained largely unchanged (Fig. 1h and Fig. S2d). Both IL-7 and IL-15 are γc family cytokines, which play critical roles in T cell homeostasis and share STAT5 as a major signaling pathway [9]. Therefore, we next explored whether STAT5 activation suppresses CD4+CD8αα+ T cell differentiation downstream of IL-7 and IL-15. To this end, we analyzed the SI IELs of mice expressing constitutively active STAT5 (STAT5-CATg). In these mice, we observed a dramatic loss of CD4+CD8αα+ IELs (Figs. 1k, j and Fig. S3c), while both the frequency and number of conventional T cells were substantially increased (Fig. S3a, S3b). Notably, the frequency of CD8αα+ IEL T cells was unaffected (Fig. S3d), indicating that the inhibitory effect of activated STAT5 was limited to CD4+CD8αα+ IELs. Collectively, these results revealed a previously unappreciated role for the homeostatic γc family cytokines IL-7 and IL-15 in constraining the induction of CD4+CD8αα+ T cells in the SI epithelium.

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Acknowledgements

This work was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research.

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  1. Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Can Li, Praveen Prakhar & Jung-Hyun Park

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  1. Can Li
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CL performed experiments, analyzed data, and wrote the paper. PP performed experiments and analyzed data. JHP directed the study and wrote the paper.

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Correspondence to Jung-Hyun Park.

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Li, C., Prakhar, P. & Park, JH. The homeostatic γc cytokines IL-7 and IL-15 suppress the induction of CD4+CD8αα+ intraepithelial T cells in the gut. Cell Mol Immunol 19, 751–753 (2022). https://doi.org/10.1038/s41423-022-00868-z

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