Down-Regulation of HLA-C Expression on Melanocytes May Contribute to the Therapeutic Efficacy of UVB Phototherapy in Psoriasis.

UVB phototherapy effectively treats psoriasis. Although it suppresses both innate and adaptive immunity, it remains unclear why UVB irradiation is primarily effective for T-cell-mediated but not inflammatory skin diseases of other etiologies. Using a Vα3S1/Vβ13S1 T-cell receptor (TCR) from a lesional psoriatic CD8+ T-cell clone, we recently demonstrated that in psoriasis, the major psoriasis risk allele HLA-C*06:02 mediates an autoimmune response of CD8+ T-cells against melanocytes by presenting a melanocyte autoantigen. We now investigate the effect of UVB irradiation on melanocyte immunogenicity using the psoriatic Vα3S1/Vβ13S1 TCR in a reporter assay. The immunogenicity of melanocytes for the Vα3S1/Vβ13S1 TCR depended on the up-regulation of HLA-C expression by IFN-γ. UVB irradiation reduced the stimulatory capacity of IFN-γ-conditioned melanocytes for the Vα3S1/Vβ13S1 TCR by suppressing key IFN-γ-induced MHC-class I transcriptional regulators (STAT1, IRF1, NLRC5), the HLA-C-specific transcription factor Oct1, and by inducing miR-148a, which specifically inhibits HLA-C expression. This resulted in the suppression of the IFN-γ-induced expression of HLA-class I molecules and, in particular, an almost complete loss of HLA-C expression. We conclude that suppression of the inflammatory increase in HLA-class I expression and antigen-presentation may contribute to the efficacy of UVB phototherapy in T-cell-mediated skin diseases. The pronounced downregulation of HLA-C on melanocytes could render psoriasis, as HLA-C-associated disease, particularly susceptible to this effect.