Exploring mechanisms that govern immune homeostasis in skin

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An important finding that led to my laboratory's current theme of tissue-immune crosstalk was elucidating how the Langerhans cell network was maintained by hair follicles (HFs). We discovered that HFs were immunologically active structures that, upon sensing mechanical stress, produced chemokines to attract Langerhans precursors and served as a gateway for their repopulation into epidermis (Nagao et al, Nat Immunol 2012). This finding represented a novel concept of how tissue-specific signals communicate with immune cells to maintain immunological homeostasis. We expanded the above findings by demonstrating that HFs produced cytokines that enabled the persistence of memory T cells in the epidermis during homeostasis, inflammation, and after malignant transformation (Adachi et al, Nat Med 2015). We also studied host-microbe interactions in the context of atopic dermatitis (AD) by generating a mouse model of AD that spontaneously developed dysbiosis predominated by S. aureus, a feature that recapitulates human AD. We determined S. aureus to be a crucial driver of eczema formation, providing an answer to a long-standing clinical question, and further demonstrated that the metalloproteinase ADAM17-EGF receptor signaling axis regulated the skin surface microbiome via EGF receptor signaling (Kobayashi et al, Immunity 2015). Expanding upon these findings, we recently discovered that HF and innate lymphoid cells (ILC) in the epidermis engaged in bilateral communication that regulated the skin microbiome by controlling sebaceous gland functions (Kobayashi et al, Cell 2019). Most recently, we determined that altered host-microbial symbiosis at the follicular opening was mediated by ADAM10-Notch signaling axis, the disruption of which in type I interferon (IFN)-responsive upper HF cells led to follicular dysbiosis predominated by Corynebacterium spp, further resulting in inflammatory destruction of the HFs mediated by a subset of group 2 ILCs (Sakamoto et al, Immunity 2021). The irreversible loss of HF stem cells in this mouse model was reminiscent of cicatricial alopecia in humans, implicating the involvement of ILCs in disease pathophysiology. Taken together with our findings in mice that lack ADAM17 from the epidermis (Kobayashi et al, Immunity 2015), we established that the epidermal keratinocytes utilize distinct mechanisms to regulate the microbiome; the interfollicular epidermis utilizes ADAM17-EGFR signaling axis to regulate S. aureus colonization, whereas the HFs utilize ADAM10-Notch signaling to regulate Corynebacterium spp colonization and the disruption of either pathway leads to pathological inflammation that is driven by dysbiosis. Considering the differential type I IFN responsiveness that HF compartments displayed (Sakamoto et al, Immunity 2021), we sorted keratinocytes subsets from poly(I:C) treated mice and found that keratinocyte subsets from the interfollicular epidermis and HFs exhibited distinct transcriptomic shifts when exposed to type I IFN (Sakamoto et al, J Invest Dermatol, 2022). We have also published a detailed protocol that enables the scientific community to employ the techniques we utilize to analyze the skin (Sakamoto et al, STAR Protocol, 2022).