Commensal Microbes and Hair Follicle Morphogenesis Coordinately Drive Treg Migration into Neonatal Skin

Abstract

SUMMARY Regulatory T cells (Tregs) are required to establish immune tolerance to commensal microbes. Tregs accumulate abruptly in the skin during a defined window of postnatal tissue development. However, the mechanisms mediating Treg migration to neonatal skin are unknown. Here we show that hair follicle (HF) development facilitates the accumulation of Tregs in neonatal skin and that upon skin entry these cells localize to HFs, a primary reservoir for skin commensals. Further, germ-free neonates had reduced skin Tregs indicating that commensal microbes augment Treg accumulation. We identified Ccl20 as a HF-derived, microbiota-dependent chemokine and found its receptor, Ccr6, to be preferentially expressed by Tregs in neonatal skin. The Ccl20-Ccr6 pathway mediated Treg migration in vitro and in vivo. Thus, HF morphogenesis, commensal microbe colonization, and local chemokine production work in concert to recruit Tregs into neonatal skin, thereby establishing this tissue Treg niche early in life.

Skin microbiota–host interactions

“…Although little is understood about the factors that regulate the acquisition of skin microbes at birth, regulatory T cells, which are highly enriched in the skin tissue, have been proposed to control early dialogue with the microbiota. Indeed, colonization of mouse skin with S. epidermidis early in life (but not later) induces tolerance to the same microbe in adulthood 61 and promotes accumulation of S. epidermidis -specific regulatory T cells in neonatal skin 62 .…”

Homeostatic Control of Sebaceous Glands by Innate Lymphoid Cells Regulates Commensal Bacteria Equilibrium

“…Recent work has established that hair follicles not only form physical barriers by producing hair shafts but also mediate immune cell homeostasis by supporting the recruitment and residency of immune cells including Langerhans cells, effector memory, and regulatory T cells (Nagao et al, 2012) (Adachi et al, 2015) (Scharschmidt et al, 2017). These studies, together with the reliance of ILCs on hair follicles reported herein, suggest that hair follicles are central to tissue-immune crosstalk in skin, but this is not unidirectional; hair follicles in turn rely on monocytes for quorum sensing-mediated regeneration (Chen et al, 2015), on regulatory T cells for stem cell maintenance (Ali et al, 2017), and, as demonstrated in this study, on ILCs for sebaceous gland control.…”

‘Layered immunity’ and the ‘neonatal window of opportunity’ – timed succession of non‐redundant phases to establish mucosal host–microbial homeostasis after birth

“…At mucosal surfaces, the establishment of tolerance to microbiota‐, diet‐ and environment‐derived antigens is characterized by an expansion of regulatory T (Treg) cells . Interestingly, the expansion of Treg cells in skin and lung (week 2 and 3, respectively) induced by exposure to commensal bacteria precedes that in the gut (week 4) .…”

“…Also, the origin of the mucosal Treg cells is different between the three locations – the early Treg cell wave detected in the hair follicles of the skin is recruited in a CCR6‐dependent manner from the thymus. Lung Treg cells that mediate tolerance do not express the transcription factor Helios and are presumably induced in the periphery . Whereas the neonatal host harbors thymus‐derived Treg cells in the secondary lymphoid tissues of the intestine, microbiota‐dependent peripherally generated Treg cells that express the transcription factor retinoic acid receptor‐related orphan receptor γ t only expand in the 4th week of life …”