Development and function of skin-homing invariant natural killer T cells

Abstract

Abstract Invariant natural killer T (iNKT) cells are innate-like T cells that express restricted T cell receptors (TCR) to recognize self and foreign lipid antigens. Distinct iNKT subsets can quickly produce numerous cytokines such as interferon (IFN)-g (iNKT1), interleukin (IL)-4 (iNKT2), and IL-17 (iNKT17) to regulate immune responses in microbial infection, allergic disease, autoimmune disease and cancer. Different iNKT cell subsets have unique transcription factor profiles such as T-bet, PLZF and RORgt that determine their cytokine-producing abilities. However, mechanisms directing the tissue localization preference of different iNKT cell subsets are not well understood. Using a novel strain of CCR10-knockout (KO)/EGFP-knockin (KI) reporter mice, we found that the skin-homing chemokine receptor CCR10 is highly upregulated in iNKT cells during their thymic development stages. Analysis of cytokine production in stimulated thymic iNKT cells demonstrated that CCR10+ iNKT cells are predominantly iNKT2 cells producing IL-4, implying that iNKT2 cells are preferentially programmed in the thymus to migrate into the skin. Confirming this, CCR10-expressing iNKT2 cells are enriched in the skin at the steady state. Taken together, these findings suggest that intrathymic programming orchestrate generation of skin-homing innate-like iNKT cells with specific functional potentials to provide immediate protection of the border tissue.