Identification of UVB-induced TREM-1-positive tolerogenic dendritic cells and TREM-1 signaling as a target in the prevention of UVB-induced immune suppression and skin carcinogenesis.

UVB-induced dysfunction of dendritic cells (DCs) is a key mechanism for UVB-induced immune suppression, a major risk factor for skin cancer development. Mechanisms remain to be fully understood despite numerous efforts. This study found that the signaling pathway of TREM-1 (triggering receptor expressed on myeloid cells 1) was a top-upregulated canonical pathway in mouse and human skin after UVB. Blocking TREM-1 with an antagonistic peptide LP-17 significantly reversed UVB-induced suppression of immune responses, suppressed UVB-induced skin carcinogenesis, and prevented the UVB-induced suppression of antigen-specific CD8+ Tc1 and Tc17 effector cells. Further studies defined a TREM-1+ tolerogenic DC subset in the draining lymph nodes, which was induced by UVB. The conditional knockout of the Trem1 gene in CD11c+ DCs abolished UVB-induced suppression of contact hypersensitivity responses. In contrast, it did not affect the immune response in mice that were not exposed to UVB. Mechanistically, blocking TREM-1 significantly increased the expression level of the activation markers CD80 and CD86 by UVB-induced TREM-1+ DCs. In conclusion, our studies have identified a UVB-induced TREM-1+ tolerogenic DC subset and demonstrated an important mechanism for UVB-induced immune suppression and skin carcinogenesis.