TGFβ1 Overexpression by Keratinocytes Alters Skin Dendritic Cell Homeostasis and Enhances Contact Hypersensitivity

Overexpression of transforming growth factor beta-1 (TGF beta 1) in mouse epidermis causes cutaneous inflammation and keratinocyte hyperproliferation. Here we examined acute effects of TGF beta 1 overproduction by keratinocytes on skin dendritic cells (DCs). TGF beta 1 induction for 2 and 4 days increased the numbers and CD86 expression of B220(+) plasmacytoid DCs (pDCs) and CD207(+)CD103(+), CD207(-)CD103(-)CD111D(+), and CD207(-)CD103(-)CD11b(-) dermal DCs (dDCs) in skin-draining lymph nodes (SDLNs). The dermis of TGF beta 1-overexpressing mice had significantly more pDCs, CD207(+)CD103(+) dDCs, and CD207(-)CD11b(+) dDCs in the absence of increased dermal proliferation. Application of dye, tetramethyl rhodamine iso-thiocyanate (TRITC), in dibutylpthalate (DBP) solution after TGF beta 1 induction increased the numbers of TRITC(+)CD207(-) dDCs in SDLNs, and augmented TRITC/DBP-induced Langerhans cell (LC) migration 72 hours post TRITC treatment. Consistent with this, LC migration was increased in vitro by TGF beta 1 overexpression in skin explants and by exogenous TGF beta 1 in culture media. Transient TGF beta 1 induction during DNFB sensitization increased contact hypersensitivity responses by 1.5-fold. Thus, elevated epidermal TGF beta 1 alone is sufficient to alter homeostasis of multiple cutaneous DC subsets, and enhance DC migration and immune responses to contact sensitizers. These results highlight a role for keratinocyte-derived TGF beta 1 in DC trafficking and in the initiation of skin inflammation. Journal of Investigative Dermatology (2013) 133, 135-143; doi:10.1038/jid.2012.241; published online 26 July 2012