ROR?t inhibition selectively targets IL-17 producing human iNKT and ?d-T cells enriched in Spondyloarthritis while preserving IL-22 responses

Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). ROR?t, the key Thelper17 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and ?d-T cells, but how they contribute to disorders such as SpA is still unclear. Here we describe the presence of particular ROR?t+T-betloPLZF- iNKT and ?d-hi T cell subsets in healthy peripheral blood. ROR?t+ iNKT and ?d-hi T cells showed profound IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and ?d-T cells showed a unique Th17 skewed phenotype and gene expression profile. Strikingly, ROR?t inhibition blocked ?d17 and iNKT17 cell function while selectively sparing IL-22+ subsets. Overall, these findings highlight a unique diversity of human ROR?t+ T cells and underscore the potential of ROR?t antagonism to modulate aberrant type 17 responses. Overall design: iNKT (CD3+TCRVb11+6B11+), ?d-T (CD3+TCR?d+) cells and Tconv (CD3+CD161-; negative for iNKT and ?d-T markers) cells were sorted from peripheral blood samples of SpA patients (n=7) and RA patients (n=5). Sequence-libraries of each sample were sequenced on a NextSeq500 system (Illumina).