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Hair follicle–derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma

Abstract

The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis through chemokine production. We demonstrate that CD4+ and CD8+ skin-resident memory T cells (TRM cells), which are responsible for long-term skin immunity, reside predominantly within the hair follicle epithelium of the unperturbed epidermis. TRM cell tropism for the epidermis and follicles is herein termed epidermotropism. Hair follicle expression of IL-15 was required for CD8+ TRM cells, and IL-7 for CD8+ and CD4+ TRM cells, to exert epidermotropism. A lack of either cytokine in the skin led to impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4+ TRM lymphoma cell localization depended on the presence of hair follicle–derived IL-7. These findings implicate hair follicle–derived cytokines as regulators of malignant and non-malignant TRM cell tissue residence, and they suggest that the cytokines may be targeted therapeutically in inflammatory skin diseases and lymphoma.

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Figure 1: Epidermotropic CD4+ and CD8+ TRM cells associate with hair follicles.
Figure 2: Epidermotropic TRM cells require hair follicle–derived cytokines.
Figure 3: Impaired CHS responses in the absence of hair follicle–derived cytokines.
Figure 4: Generation of a model of T cell lymphoma with skin involvement.
Figure 5: CD4+ TRM lymphoma cells depend on hair follicle–derived IL-7 to exhibit epidermotropism.
Figure 6: IL-7 and IL-15 expression in human hair follicles from normal scalp and cutaneous T cell lymphoma.

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Acknowledgements

We thank M. Ohyama for helpful discussion on human hair follicles; N. Sakai, K. Eguchi and S. Sato (Keio University School of Medicine) for their technical assistance; H. Kong (National Institutes of Health) for their discussions on human CTCL; Y. Madokoro (Keio University School of Medicine) for human CTCL immunohistochemical staining; T. Kitamura (University of Tokyo) for providing the retroviral vector pMXs-IG and Plat-E cells; J. Takeda (Osaka University) for providing K5-Cre mice; D.H. Kaplan (University of Minnesota) for providing Langerin-DTA mice; and B.E. Clausen (Johannes Gutenberg University of Mainz) for providing Langerin-DTR mice. This work was supported by the Japan Society for the Promotion of Science, The Kanae Foundation for the Promotion of Medical Science, the Japanese Society for Investigative Dermatology's (JSID's) Fellowship Shiseido Award and the NIH NCI Intramural Research Programs.

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Contributions

T.A. and K.N. conceived of and designed all experiments. Experiments were performed by T.A. with the assistance of T.K.; E.S. and H.S. provided Cdkn2a−/− mice and assisted with retroviral transduction; T.Y. assisted with immunohistochemical staining; K.I. provided Il7-floxed mice; S.P. provided human CTCL samples; M.A. discussed the data and provided administrative support; K.N. guided the project; and T.A. and K.N. wrote the manuscript.

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Correspondence to Keisuke Nagao.

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The authors declare no competing financial interests.

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Adachi, T., Kobayashi, T., Sugihara, E. et al. Hair follicle–derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. Nat Med 21, 1272–1279 (2015). https://doi.org/10.1038/nm.3962

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