Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids

Abstract

IL-17A-expressing CD4+ T cells (Th17 cells) are generally regarded as key effectors of autoimmune inflammation. However, not all Th17 cells are pro-inflammatory. Pathogenic Th17 cells that induce autoimmunity in mice are distinguished from nonpathogenic Th17 cells by a unique transcriptional signature, including high Il23r expression, and these cells require Il23r for their inflammatory function. In contrast, defining features of human proinflammatory Th17 cells are unknown. We show that pro-inflammatory human Th17 cells are restricted to a subset of CCR6+CXCR3hiCCR4loCCR10-CD161+ cells that transiently express c-Kit and stably express P-glycoprotein (P-gp)/multi-drug resistance type 1 (MDR1). In contrast to MDR1- Th1 or Th17 cells, MDR1+ Th17 cells produce both Th17 (IL-17A, IL-17F, and IL-22) and Th1 (IFN-γ) cytokines upon TCR stimulation and do not express IL-10 or other anti-inflammatory molecules. These cells also display a transcriptional signature akin to pathogenic mouse Th17 cells and show heightened functional responses to IL-23 stimulation. In vivo, MDR1+ Th17 cells are enriched and activated in the gut of Crohn's disease patients. Furthermore, MDR1+ Th17 cells are refractory to several glucocorticoids used to treat clinical autoimmune disease. Thus, MDR1+ Th17 cells may be important mediators of chronic inflammation, particularly in clinical settings of steroid resistant inflammatory disease. © 2014 Ramesh et al.