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

Abstract 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 using human healthy controls (HC) and AD patients' skin and blood. CXCR4 and CXCL12 expressions 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 AD mouse models using CXCR conditionally deficient or CXCL12 transgenic mice. Results CXCR4 and its cognate ligand CXCL12 were significantly upregulated in human AD skin by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin and were consistently elevated in our AD mouse models. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Predominant skin NKT cells were CXCR4+ and CD69+, similar to tissue-resident memory T (TRM) cells. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in 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+ NKTRM/CXCL12+ cell cluster, which developed in acute and chronic allergic inflammation in our AD mouse models. Conclusions CXCR4+ NKTRM cells may form a niche that contributes to atopic dermatitis, where CXCL12 is highly expressed.