Abstract
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.