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.