title: 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 pro-inflammatory Th17 cells are unknown. We show that pro-inflammatory human Th17 cells are restricted to a subset of CCR6(+)CXCR3(hi)CCR4(lo)CCR10(-)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.
authors.affiliation: Tempero Pharmaceuticals, Inc., 200 Technology Square, Suite 602, Cambridge, MA 02139.
authors.forename: Radha
authors.initials: R
authors.lastname: Ramesh
authors.forename: Lina
authors.initials: L
authors.lastname: Kozhaya
authors.forename: Kelly
authors.initials: K
authors.lastname: McKevitt
authors.forename: Ivana M
authors.initials: IM
authors.lastname: Djuretic
authors.forename: Thaddeus J
authors.initials: TJ
authors.lastname: Carlson
authors.forename: Maria A
authors.initials: MA
authors.lastname: Quintero
authors.forename: Jacob L
authors.initials: JL
authors.lastname: McCauley
authors.forename: Maria T
authors.initials: MT
authors.lastname: Abreu
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sundrud
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D046228:Microarray Analysis; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D007371:Interferon-gamma