Autocrine/paracrine TGFβ1 is required for the development of epidermal Langerhans cells

Langerhans cells (LCs) are bone marrow (BM)-derived epidermal dendritic cells (DCs) that develop from precursors found in the dermis. Epidermal LCs are absent in transforming growth factor (TGF) beta 1-deficient mice. It is not clear whether TGF beta 1 acts directly on LC precursors to promote maturation or whether it acts on accessory cells, which in turn affect LC precursors. In addition, the physiologic source of TGF beta 1 is uncertain because BM chimera experiments showed that neither hematopoietic nor nonhematopoietic-derived TGF beta 1 is required for LC development. To address these issues, we created mice transgenic for a bacterial artificial chromosome (BAC) containing the gene for human Langerin into which Cre recombinase had been inserted by homologous recombination (Langerin-Cre). These mice express Cre selectively in LCs, and they were bred to floxed TGF beta RII and TGF beta 1 mice, thereby generating mice with LCs that either cannot respond to or generate TGF beta 1, respectively. Langerin-Cre TGF beta RII mice had substantially reduced numbers of epidermal LCs, demonstrating that TGF beta 1 acts directly on LCs in vivo. Interestingly, Langerin-Cre TGF beta 1 mice also had very few LCs both in the steady state and after BM transplantation. Thus, TGF beta 1 derived from LCs acts directly on LCs through an autocrine/paracrine loop, and it is required for LC development and/or survival.