Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis

Background: Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD). Objective: We aimed to investigate the role of NKT cells in AD development, especially in skin. Methods: Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy–controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4⁺ NKT cells was further evaluated in models of mice with AD by using CXCR4–conditionally deficient or CXCL12 transgenic mice. Results: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4⁺ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4⁺ and CD69⁺. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4⁺ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4⁺ tissue-resident NKT cells/CXCL12⁺ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. Conclusions: CXCR4⁺ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.