Multi-drug resistant Th17 cells: new players in autoimmune and steroid-resistant inflammation (HUM8P.351)

Abstract

Abstract Th17 cells are generally regarded as key effectors of autoimmune disease. However, not all Th17 cells are pro-inflammatory. Furthermore, the defining features of "pathogenic" Th17 cells in humans are unknown. We have found that pro-inflammatory human Th17 cells are restricted to a subset of CCR6+ CXCR3(hi) CCR4(lo) CCR10- CD161+ T cells that expresses the drug transporter multi-drug resistance-1. Unlike MDR1- human memory T cell subsets, MDR1+ Th17 cells produce both Th17 and Th1 cytokines upon stimulation; do not express IL-10 or other anti-inflammatory molecules; express high levels of IL23R as well as other genes selectively expressed by pathogenic mouse Th17 cells; and display heightened responsiveness to IL-23 stimulation. In vivo, MDR1+ Th17 cells accumulate in the gut of patients with active Crohn's Disease, where they display a marked pro-inflammatory transcriptional signature relative to local MDR1- effector T cells. In addition, MDR1+ Th17 cells are refractory to the immunosuppressive effects of several steroids used to treat autoimmune disease in the clinic. Thus, MDR1+ Th17 cells may be important mediators of autoimmune inflammation, particularly in clinical settings of steroid-resistant disease.