9-cis-Retinoic acid induces a distinct regulatory dendritic cell phenotype that modulates murine delayed-type allergy.

BACKGROUND: Hand eczema, which is frequently caused by delayed-type allergy, is treated with 9-cis-retinoic acid (9cisRA). However, knowledge on how 9cisRA modulates skin immunity is sparse. OBJECTIVE: As dendritic cells (DCs) are central in the pathogenesis of contact allergy, we investigated 9cisRA modulation of DC function in murine contact hypersensitivity (CHS). METHODS: 9cisRA-differentiated DCs (9cisRA-DCs) were analysed for phenotype and function. In vivo 9cisRA-DCs were tested in the CHS model. RESULTS: 9cisRA induces the differentiation of a distinct CD103- CD207- regulatory DC phenotype. CD11c+ DCs differentiated with 9cisRA have lower expression of major histocompatibility complex-II and costimulatory molecules, but conversely have higher expression of the inhibitory coreceptor PD1-L. 9cisRA-DC culture does not induce the expression of proinflammatory cytokines, but strongly enhances osteopontin (OPN) secretion. 9cisRA-DCs are compromised in the induction of T cell proliferation in vitro, but efficiently convert naive T cells into regulatory T cells (Tregs). Notably, OPN-deficient 9cisRA-DCs show a loss of Treg-inducing function, which is re-established by substituting OPN. In vivo, in allergic mice, allergen-primed 9cisRA-DCs suppress allergic inflammation and induce Treg accumulation in skin draining lymph nodes. CONCLUSIONS: This study describes 9cisRA-mediated differentiation of a distinct DC phenotype that relies on OPN for Treg transformation and suppresses established CHS through Treg induction.