Summary Skin-resident dendritic cells (DC) are well positioned to encounter cutaneous pathogens and are required for the initiation of adaptive immune responses. There are at least 3 subsets of skin DC — Langerhans cells (LC), Langerin+ dermal DC (dDC), and classic dDC. Whether these subsets have distinct or redundant function in vivo is poorly understood. Using a Candida albicans skin infection model, we have shown that direct presentation of antigen by LC is necessary and sufficient for the generation of antigen-specific T helper-17 (Th17) cells but not for the generation of cytotoxic lymphocytes (CTL). In contrast, Langerin+ dDC are required for the generation of antigen specific CTL and Th1 cells. Langerin+ dDC also inhibited the ability of LC and classic DC to promote Th17 responses. This work demonstrates that skin-resident DC subsets promote distinct and opposing antigen-specific responses.

Langerhans cells (LC) are a subset of skin-resident DC that reside in the epidermis as immature DC where they acquire antigen. A key step in the life cycle of LC is their activation into mature DC in response to various stimuli including epicutaneous sensitization with hapten and skin infection with C. albicans. Mature LC migrate to the skin-draining LN where they present antigen to CD4 T cells and modulate the adaptive immune response. LC migration is thought to require the direct action of IL-1β and IL- 18 on LC. In addition, TLR-ligands are present in C. albicans and hapten sensitization produces endogenous TLR-ligands. Both could contribute to LC activation. We generated Langerin-Cre MyD88fl mice in which LC are insensitive to IL-1 family members and most TLR-ligands. LC migration in the steady-state, after hapten sensitization and after infection with C. albicans was unaffected. Contact hypersensitivity in Langerin-Cre MyD88fl mice was similarly unaffected. Interestingly, in response to C. albicans infection these mice displayed reduced proliferation of antigen-specific CD4 T cells and defective Th17 subset differentiation. Surface expression of co-stimulatory molecules was intact on LC but expression of IL-1β, IL-6, and IL-23 was reduced. Thus, sensitivity to MyD88-dependent signals is not required for LC migration but is required for the full activation and function of LC in the setting of fungal infection.

Tissue immunosurveillance is an important mechanism to prevent cancer. Skin treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), followed by the tumor promoter 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), is an established murine model for squamous cell carcinoma (SCC). However, the innate immunological events occurring during the initiation of chemical carcinogenesis with DMBA remain elusive. Here, we discovered that natural killer (NK) cells and Langerhans cells (LC) cooperate to impair this oncogenic process in murine skin. The depletion of NK cells or LC caused an accumulation of DNA-damaged, natural killer group 2D-ligand (NKG2D-L) expressing keratinocytes and accelerated tumor growth. Notably, the secretion of TNFα mainly by LC promoted the recruitment of NK cells into the epidermis. Indeed, the TNFα-induced chemokines CCL2 and CXCL10 directed NK cells to DMBA-treated epidermis. Our findings reveal a novel mechanism how innate immune cells cooperate in the inhibition of cutaneous chemical carcinogenesis.

Activation of hedgehog/glioma‐associated oncogene homolog (HH/GLI) signaling induces basal cell carcinoma (BCC) and establishes an immunosuppressive tumor microenvironment. HH/GLI signaling inhibits the activity of antitumoral T cells via programmed death ligand 1/programmed death‐1 immune checkpoint signaling and the recruitment of immunosuppressive regulatory T cells. BCCs also show strong infiltration with antitumoral neutrophils. The data support the evaluation of combination treatments with HH inhibitors and immune checkpoint blockers.