nucleotide exchange factor and is essential for transducing T cell receptor signals, suggesting its critical role in the development and activation of T cells.28,29VAV1-/- mice were resistant to MOG-induced experimental autoimmune encephalomyelitis (EAE) due to defective priming and expansion of CD4+ and CD8+ T cells.30 The IDH1 gene encodes isocitrate dehydrogenase 1, which catalyzes the NADP-dependent conversion of isocitrate to ɑ-ketoglutarate. Xu et al. reported that knockdown of both IDH1 and IDH2 reduced Th17 cell differentiation and increased Foxp3 expression.31 Aso et al.suggested that itaconate inhibited IDH1/2, which altered the chromatin accessibility of essential transcription factors at IL-17a andFoxp3 loci, leading to decreased IL-17A and increased Foxp3 expression.32 The RAB35 gene encodes Ras-related protein functioning in vesicle formation, motility, docking, and fusion.33,34 Yang et al. reported that Th2 cells deficient in Rab35 exhibited enhanced TCR-mediated effector function.35 Previous studies suggested that the differentiation and function of Tregs are correlated with the strength of TCR signaling.36-38 Our study found UVB significantly inhibited these three negative regulators, which may affect TCR signaling during the antigen stimulation and result in Treg differentiation.
Single-cell TCR sequencing from patient PBMCs revealed that UVB enhanced clonal expansion in Tregs (Fig ure 6E-G). Compared to other T cell subsets (naive T, memory T, and effector T cells), Tregs exhibited a greater increase in clone size after UVB treatment, suggesting potential induction from other CD4+ T cells (Fig ure 6F). Analysis of individual samples demonstrated clonal expansion of Tregs in all cases (Fig ure 6G). The importance of clonal expansion of antigen-specific Tregs has been shown in patients with diabetes.39 Specifically, individuals with long-standing anti-islet autoimmunity who do not progress to overt diabetes exhibit a higher frequency of insulin-specific Tregs compared to both healthy individuals and those with diabetes onset.39
The relatively small sample size of psoriasis patients in UVB trial constrains our high-dimensional genomic data analyses. While clinical responses to UVB vary among individuals, CyTOF analysis from PBMCs revealed a statistically significant increase in activated Tregs post-UVB treatment (Fig ure 1D). While the role of Tregs in psoriasis remains debated40-42, we observed a negative correlation between the proportion of activated Tregs and psoriasis severity in a significant dose-dependent manner(Fig ure 4A,B). The limited input cell numbers for scRNA and scTCR sequencing affected the depth of the transcriptomic analysis and the assessment of clonal expansion. Nevertheless, integrating genomic data from mouse and human samples sheds light on the differential gene expression patterns and offers a better understanding of the mechanism underlying the induction of antigen-specific Tregs by UVB.
In conclusion, our study provides evidence that the proportion of activated Tregs in peripheral blood may predict individual responses in UVB trial. Our scRNA/scTCR sequencing findings demonstrate that UVB exposure can induce Treg differentiation from other CD4+ T cell subsets and stimulate Treg clonal expansion, providing a novel mechanism underlying UVB-mediated antigen-specific immune suppression. The three significantly downregulated genes (VAV1 , IDH1 , and Rab35 ) represent potential therapeutic targets to induce antigen-specific Tregs in future translational studies.