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

R Ramesh, L Kozhaya, K McKevitt, IM Djuretic… - Journal of Experimental …, 2014 - rupress.org
R Ramesh, L Kozhaya, K McKevitt, IM Djuretic, TJ Carlson, MA Quintero, JL McCauley
Journal of Experimental Medicine, 2014rupress.org
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 pro-
inflammatory Th17 cells are unknown. We show that pro-inflammatory human Th17 cells are …
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 pro-inflammatory Th17 cells are unknown. We show that pro-inflammatory human Th17 cells are restricted to a subset of CCR6+CXCR3hiCCR4loCCR10CD161+ 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.
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