Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Langerhans cells (LCs) are skin-resident dendritic cells (DC) located in the epidermis that migrate to skin-draining lymph nodes during the steady state and in response to inflammatory stimuli. TGF-beta 1 is a critical immune regulator that is highly expressed by LCs. The ability to test the functional importance of LC-derived TGF-beta 1 is complicated by the requirement of TGF-beta 1 for LC development and by the absence of LCs in mice with an LC-specific ablation of TGF-beta 1 or its receptor. To overcome these problems, we have engineered transgenic huLangerin-CreER(T2) mice that allow for inducible LC-specific excision. Highly efficient and LC-specific expression was confirmed in mice bred onto a YFP Cre reporter strain. We next generated huLangerin-CreER(T2) x TGF-beta RIIfl and huLangerin-CreER(T2) x TGF-beta 1(fl) mice. Excision of the TGF beta RII or TGF beta 1 genes induced mass migration of LCs to the regional lymph node. Expression of costimulatory markers and inflammatory cytokines was unaffected, consistent with homeostatic migration. In addition, levels of p-SMAD2/3 were decreased in LCs from wild-type mice before inflammation-induced migration. We conclude that TGF-beta 1 acts directly on LCs in an autocrine/paracrine manner to inhibit steady-state and inflammation-induced migration. This is a readily targetable pathway with potential therapeutic implications for skin disease.