021 CXCL13-producing peripheral T helper cells as potential mediators of photosensitivity in dermatomyositis

Abstract

Dermatomyositis (DM) is a rare autoimmune disease that causes photosensitivity, disfiguring rash, and pruritus. Type I interferons (IFN-Is) are expressed in lesional (L) skin of DM, suggesting their role in disease pathogenesis. Using suction blistering on both L and non-lesional (NL) skin of treatment-naïve patients with DM followed by single-cell RNA sequencing (scRNA-seq) and flow cytometry, we found a distinct population of T cells expressing high levels of CXCL13, only in L DM. Their immunophenotype (CD4+/PD-1hi/CXCR5-) was characteristic of T peripheral helper (Tph) cells, a new subset of T cells recently described to drive autoimmunity in rheumatoid arthritis via CXCL13 mediated recruitment of B cells to synovium. However, consistent with previous reports, we did not find any B cells infiltrating L DM skin. Intriguingly, we observed high expression of CXCR5 on a subset of CD8+ T cells in both DM blood and L skin, suggesting CXCL13 promotes recruitment of cytotoxic CD8+ T cells to the inflamed skin. ELISA on the interstitial skin fluid confirmed higher levels of CXCL13 in L DM than NL and healthy (p<0.001), and immunohistochemistry highlighted CXCL13 staining colocalizing within perivascular CD4+ T cells. Using gene set enrichment analysis in our scRNA-seq data, we identified a robust IFN-I signature in Tph cells in DM skin. Further, we found that CD4+ T cells from DM blood displayed a significantly higher CXCL13 expression in response to IFNA than those from healthy subjects in vitro (p<0.01). Moreover, we observed that keratinocytes (KCs) isolated from L DM exhibit an enhanced IFNA expression in response to UVB than healthy in vitro, indicating an exaggerated IFN-I response to UVB in DM KCs induces differentiation of CXCL13-producing Tph cells in the skin, leading to the recruitment of circulating cytotoxic CD8+ T cells. These findings suggest a novel role for the IFN-I/CXCL13 axis in DM pathogenesis and its potential contribution to photosensitivity.