Skin-Resident Natural Killer T Cells Induce Cutaneous Allergic Inflammation In Atopic Dermatitis

Abstract 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). Here, we demonstrate that CXCR4 and its cognate ligand CXCL12 are significantly up-regulated in human AD skin in global transcriptomic analysis; proteomic analysis revealed that CXCR4+ NKT cells are enriched in AD skin and are consistently elevated in our AD mouse model. Adoptive transfer of allergen-specific NKT cells confer antigen-specific cutaneous inflammation, and predominant skin NKT cells are CXCR4+ and CD69+, similar to tissue-resident memory T (TRM) cells. Skin-resident NKT cells uniquely expressed CXCR4, which was confirmed using a parabiosis system. Intravital imaging showed that CXCR4+ NKT cells preferentially trafficked to a CXCL12-rich area, forming an enriched CXCR4+ NKTRM/CXCL12+ cell cluster, which developed acute and chronic allergic inflammation. CXCR4+ NKTRM cells may form a niche to develop AD, where CXCL12 is highly expressed.