Skin-resident CXCR6+ memory CD4+ T cells and dendritic cells form dermal perivascular hubs that drive relapse in allergic dermatitis.

CD4+ tissue-resident memory T (TRM) cells are crucial for relapse in allergic skin conditions. However, the mechanisms underlying their maintenance and pathogenic potential remain poorly defined. Here, across multiple models of allergic dermatitis, we identified a C-X-C chemokine receptor 6 (CXCR6+) subpopulation within CD4+ TRM cells as a distinct pathogenic subset that rapidly induces relapse. This subset is supported by C-X-C chemokine ligand 16 (CXCL16)-dependent interactions with CD301b+ conventional type 2 dendritic cells (cDC2s) for in situ maintenance. Functional blockade of the CXCL16-CXCR6 signaling pathway impaired proliferation and maintenance of CXCR6+ CD4+ TRM cells. In human atopic dermatitis (AD), CXCR6+ CD4+ TRM cells co-localized with CD301+ cDC2s in perivascular clusters even after successful anti-IL-13 therapy. These findings point to CXCR6+ CD4+ TRM cells as a pathogenic reservoir sustaining chronic and recurrent inflammation and suggest the CXCL16-CXCR6 axis as a therapeutic target to prevent relapse in allergic skin diseases.