Skin and Peripheral Lymph Node Invariant NKT Cells Are Mainly Retinoic Acid Receptor-Related Orphan Receptor γt+ and Respond Preferentially under Inflammatory Conditions

Abstract

Lymph nodes (LNs) have been long considered as comprising few invariant NKT (iNKT) cells, and these cells have not been studied extensively. In this study, we unravel the existence of stable rather than transitional LN-resident NK1.1− iNKT cell populations. We found the one resident in peripheral LNs (PLNs) to comprise a major IL-17-producing population and to express the retinoic acid receptor-related orphan receptor γt (RORγt). These cells respond to their ligand α-galactosylceramide (α-GalCer) in vivo by expanding dramatically in the presence of LPS, providing insight into how this rare population could have an impact in immune responses to infection. PLN-resident RORγt+ NK1.1− iNKT cells express concomitantly CCR6, the integrin α-chain αE (CD103), and IL-1R type I (CD121a), indicating that they might play a role in inflamed epithelia. Accordingly, skin epithelia comprise a major RORγt+ CCR6+CD103+CD121a+ NK1.1− cell population, reflecting iNKT cell composition in PLNs. Importantly, both skin and draining PLN RORγt+ iNKT cells respond preferentially to inflammatory signals and independently of IL-6, indicating that they could play a nonredundant role during inflammation. Overall, our study indicates that RORγt+ iNKT cells could play a major role in the skin during immune responses to infection and autoimmunity.