Skin microbe-dependent TSLP-ILC2 priming axis in early life is co-opted in allergic inflammation

Although early life colonization of commensal microbes contributes to long-lasting immune imprinting in host tissues, little is known regarding the pathophysiological consequences of postnatal microbial tuning of cutaneous immunity. Here, we show that postnatal exposure to specific skin commensal Staphylococcus lentus (S. lentus) promotes the extent of atopic dermatitis (AD)-like inflammation in adults through priming of group 2 innate lymphoid cells (ILC2s). Early postnatal skin is dynamically populated by discrete subset of primed ILC2s driven by microbiota-dependent induction of thymic stromal lymphopoietin (TSLP) in keratinocytes. Specifically, the indole-3-aldehyde-producing tryptophan metabolic pathway, shared across Staphylococcus species, is involved in TSLP-mediated ILC2 priming. Furthermore, we demonstrate a critical contribution of the early postnatal S. lentus-TSLP-ILC2 priming axis in facilitating AD-like inflammation that is not replicated by later microbial exposure. Thus, our findings highlight the fundamental role of time-dependent neonatal microbial-skin crosstalk in shaping the threshold of innate type 2 immunity co-opted in adulthood. [Display omitted] •ILC2s undergo postnatal priming depending on the skin commensal microbiota•IAld-producing Staphylococcus species induces TSLP-mediated early ILC2 priming•ILC2 priming early in life is co-opted in allergic skin inflammation in adulthood Cha and colleagues report that early postnatal colonization with skin commensal microbiota, particularly IAld-producing Staphylococcus species, induces ILC2 priming mediated by keratinocyte-derived TSLP. This early ILC2 priming during the postnatal period, actively promotes allergic skin inflammation in adulthood.