UVB Phototherapy Induces a Stress-Driven Anergy Pathway as a Novel Axis of T Cell Regulation

Introduction/Rationale: Phototherapy is widely used to treat autoimmune diseases, yet the mechanisms underlying UVB’s immune modulation remain unclear and disease specific. UVB suppresses Th1/th17 activity in vitiligo and psoriasis, but can activate immunity in lupus. We hypothesized that these diverse effects arise from a shared stress-related mechanism rather than cytokine-specific modulation. Specifically, we proposed that chronic UVB exposure induces atypical T cell activation leading to a novel form of anergy.

Methods: We combined single-cell RNA sequencing of skin-draining lymph nodes and spleen with peripheral blood analysis of vitiligo patients before and after phototherapy. Computational analyses of gene expression, transcription factor activity, and pathway enrichment were integrated with flow cytometry and RT-PCR to validate the cellular and molecular features of UVB-induced immune modulation.

Results: Chronic UVB exposure activated T cells independently of canonical TCR signaling, producing a distinct anergic state characterized by AP-1 activation in the absence of NFAT activity. We term this mechanism stress-driven anergy -a condition is the inverse of classical anergy, which arises from NFAT activation without AP-1 . It promotes expansion of ICOS⁺Ly6a⁺ activated Tregs while suppressing naïve CD4⁺, CD8⁺, and IL-17-producing γδ T cells through induction of AP-1 inhibitory genes. Type I interferon signaling emerged as a critical upstream component, sustaining AP-1–dependent activation. In human, this process cuntribute to inhibition of vitiligo-specific memory T cells following phototherapy.

Conclusion: Our findings identify stress driven anergy as a previously unrecognized regulatory axis explaining the diverse outcomes of UVB phototherapy. This mechanism reframes UVB not merely as an immunosuppressive agent but as a physiological stressor that reprograms T cell activation, offering new conceptual and therapeutic opportunities for targeted immune modulation in autoimmunity.