Uncovering a new immune tolorogenic axis in the skin across inflammation and cancer

| 01/30/2026

In this study newly published in the journal Nature Immunology, the Mei Li's team delineated a previously unknown immunoregulatory axis in which the epithelial cell–derived cytokine TSLP acts on a specific dendritic cell subset to drive the generation of regulatory T cells across both inflammatory and cancer contexts.

TSLP activates tDC2, differentiated from tDC and mature in the skin tissue/tumour site, which migrate to draining LN to promote GATA3+ effector Treg cells (eTreg) expressing OX40, ST2, CCR8, CTLA-4, CD44, ICOS and IL-10, mediating effective immune suppression. TSLP-activated tDC2 express CD24, CD8a and Thy1 on their surface, and upregulate OX40L, which is required for eTreg induction. These cells are characterized by high expression of antigen processing and presentation molecules, and enriched expression of tolerogenic molecules. Human relevance is supported by TSLP overexpression in skin cancers, and identification of tDC2 homologous cells among activated LAMP3hi DC with enriched OX40L gene expression. Our study also indicates that TSLP signals through a distinct DC population to promote GATA3+ Th2 cells producing IL-4 and IL-13, driving type-2 inflammation in an OX40L-independent manner, but the exact identity of the DC in this axis remains yet to be determined.

FOXP3⁺ regulatory T (Treg) cells are indispensable for peripheral tolerance and immune suppression, yet the mechanisms driving their generation and propagation remain incompletely defined. We previously showed that the epithelial cytokine thymic stromal lymphopoietin (TSLP) promotes GATA3⁺ effector Treg (eTreg) generation via dendritic cells (DCs), establishing an immunosuppressive microenvironment in cutaneous melanoma. The identity of the responsible tolerogenic DC subset, however, has been unclear.

In this study, we leveraged an established mouse model of skin inflammation in which topical application of MC903 induces TSLP expression, enabling us to dissect the TSLP–DC–eTreg axis. By combining advanced mouse genetic approaches with single-cell transcriptomics, lineage tracing, surface phenotyping, and functional assays, we identify a specific migratory DC2 subset derived from transitional DCs (tDC2s) as the key mediator of TSLP-driven eTreg differentiation. We further show that the tolerogenic function of these tDC2s depends on OX40L signaling, revealing a previously unrecognized immunoregulatory axis operative across inflammatory and cancer settings and is conserved in humans.

Together, our findings define a previously unrecognized tolerogenic axis and suggest that targeting the TSLP–tDC2–eTreg pathway may offer new strategies to counter tumor immune evasion or restrain pathological inflammation.

link to publication : here