Self-antigen keratin 17 presented by keratinocytes promotes T-cell autoreactivity in psoriasis.

Psoriasis is a T-cell-mediated inflammatory and autoimmune skin disease characterized by aberrant adaptive immune responses against specific autoantigens. Among the autoantigens implicated, keratin 17 (K17), an intermediate filament protein overexpressed in psoriatic keratinocytes, has been proposed to form a "K17 loop" that amplifies inflammation. However, direct evidence linking the presentation of this self-antigen to psoriatic inflammation remains limited. In this study, we identified a K17-positive keratinocyte subpopulation with enhanced antigen-presenting function in psoriatic skin. Mass spectrometry analysis revealed that activated keratinocytes express major histocompatibility complex class II molecules loaded with the K17-derived epitope and subsequently activate CD4+ T cells in a HLA-restricted manner. Using a graft-versus-host disease mouse model to validate functional K17-specific T cells, we adoptively transferred T cells into mice challenged with imiquimod and observed exacerbated psoriasis-like skin inflammation. Our findings demonstrate that keratinocytes function as nonprofessional antigen-presenting cells, mediating K17-specific T-cell responses and amplifying psoriatic inflammation. Together, this study characterizes HLA-restricted, keratinocyte-mediated K17 presentation and establishes its functional role in promoting psoriatic inflammation, suggesting that targeting K17 in keratinocyte-T-cell interactions may represent a promising therapeutic strategy.