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

Radha Ramesh, Lina Kozhaya, Kelly McKevitt, Ivana M. Djuretic, Thaddeus J. Carlson, Maria A. Quintero, Jacob L McCauley, Maria T Abreu, Derya Unutmaz, Mark S. Sundrud

Research output: Contribution to journalArticle

198 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)89-104
Number of pages16
JournalJournal of Experimental Medicine
Volume211
Issue number1
DOIs
StatePublished - Jan 1 2014

Fingerprint

Th17 Cells
P-Glycoprotein
Glucocorticoids
Multiple Drug Resistance
Interleukin-17
Interleukin-23
Inflammation Mediators
Th1 Cells
Autoimmunity
Crohn Disease
Interleukin-10
Autoimmune Diseases
Anti-Inflammatory Agents

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Ramesh, R., Kozhaya, L., McKevitt, K., Djuretic, I. M., Carlson, T. J., Quintero, M. A., ... Sundrud, M. S. (2014). Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. Journal of Experimental Medicine, 211(1), 89-104. https://doi.org/10.1084/jem.20130301

Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. / Ramesh, Radha; Kozhaya, Lina; McKevitt, Kelly; Djuretic, Ivana M.; Carlson, Thaddeus J.; Quintero, Maria A.; McCauley, Jacob L; Abreu, Maria T; Unutmaz, Derya; Sundrud, Mark S.

In: Journal of Experimental Medicine, Vol. 211, No. 1, 01.01.2014, p. 89-104.

Research output: Contribution to journalArticle

Ramesh, R, Kozhaya, L, McKevitt, K, Djuretic, IM, Carlson, TJ, Quintero, MA, McCauley, JL, Abreu, MT, Unutmaz, D & Sundrud, MS 2014, 'Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids', Journal of Experimental Medicine, vol. 211, no. 1, pp. 89-104. https://doi.org/10.1084/jem.20130301
Ramesh, Radha ; Kozhaya, Lina ; McKevitt, Kelly ; Djuretic, Ivana M. ; Carlson, Thaddeus J. ; Quintero, Maria A. ; McCauley, Jacob L ; Abreu, Maria T ; Unutmaz, Derya ; Sundrud, Mark S. / Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. In: Journal of Experimental Medicine. 2014 ; Vol. 211, No. 1. pp. 89-104.
@article{20e1a5442451434d907e7038031761ef,
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 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.",
author = "Radha Ramesh and Lina Kozhaya and Kelly McKevitt and Djuretic, {Ivana M.} and Carlson, {Thaddeus J.} and Quintero, {Maria A.} and McCauley, {Jacob L} and Abreu, {Maria T} and Derya Unutmaz and Sundrud, {Mark S.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1084/jem.20130301",
language = "English",
volume = "211",
pages = "89--104",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "1",

}

TY - JOUR

T1 - Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids

AU - Ramesh, Radha

AU - Kozhaya, Lina

AU - McKevitt, Kelly

AU - Djuretic, Ivana M.

AU - Carlson, Thaddeus J.

AU - Quintero, Maria A.

AU - McCauley, Jacob L

AU - Abreu, Maria T

AU - Unutmaz, Derya

AU - Sundrud, Mark S.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84892536761&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892536761&partnerID=8YFLogxK

U2 - 10.1084/jem.20130301

DO - 10.1084/jem.20130301

M3 - Article

C2 - 24395888

AN - SCOPUS:84892536761

VL - 211

SP - 89

EP - 104

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 1

ER -