PINK1-dependent Mitophagy Mediates CD8+ T Cell Residency and Drives Psoriatic Relapse via CCR4-CCL17/22 Recruitment

Psoriasis is a chronic inflammatory skin disease characterized by the tendency to relapse in situ. While CD8⁺ tissue-resident memory T cells are key mediators of recurrence, the mechanisms sustaining their persistence remain unclear. This study investigates whether PINK1-mediated mitophagy, orchestrated by the CCR4–CCL17/22 signaling axis, promotes CD8⁺ T cell residency. Utilizing single-cell and spatial transcriptomics, multiplex immunofluorescence on human lesions, and imiquimod-induced models in Pink1 knockout mice, we found that PINK1-mediated mitophagy is significantly upregulated during occurrence and relapse phases. High mitophagy signatures in CD8⁺ T cells correlated with increased residency. We demonstrated that epidermal Langerhans cell 2 (LC2) and CD8⁺ T cells interact via CCR4 and its ligands CCL17/22. Functional assays confirmed this LC2-CCR4 axis sustains CD8⁺ T-cell residency by driving PINK1-dependent mitophagy. Disruption of this pathway dismantled T cell persistence and alleviated recurrence in situ in murine models. In conclusion, PINK1-mediated mitophagy is a fundamental metabolic mechanism governing CD8⁺ T cell residency. Elucidating the LC2-CCL17/22-CCR4 spatial and metabolic regulatory axis offers a mechanistic foundation for targeting mitophagy to break the cycle of psoriasis relapse.