TY - JOUR
T1 - Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases
AU - van der Ploeg, Esmee K.
AU - Golebski, Korneliusz
AU - van Nimwegen, Menno
AU - Fergusson, Joannah R.
AU - Heesters, Balthasar A.
AU - Martinez-Gonzalez, Itziar
AU - Kradolfer, Chantal M. A.
AU - van Tol, Sophie
AU - Scicluna, Brendon P.
AU - de Bruijn, Marjolein J. W.
AU - de Boer, Geertje M.
AU - Tramper-Stranders, Gerdien A.
AU - Braunstahl, Gert-Jan
AU - van IJcken, Wilfred F. J.
AU - Nagtegaal, A. Paul
AU - van Drunen, Cornelis M.
AU - Fokkens, Wytske J.
AU - Huylebroeck, Danny
AU - Spits, Hergen
AU - Hendriks, Rudi W.
AU - Stadhouders, Ralph
AU - Bal, Suzanne M.
N1 - Publisher Copyright: Copyright © 2021 The Authors, some rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/29
Y1 - 2021/1/29
N2 - Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO+ ILC2s are derived from resting CD45RA+ ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO+ ILC2s and mouse iILC2s. Frequencies of CD45RO+ inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO+ ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO+ inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance.
AB - Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO+ ILC2s are derived from resting CD45RA+ ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO+ ILC2s and mouse iILC2s. Frequencies of CD45RO+ inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO+ ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO+ inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance.
UR - http://www.scopus.com/inward/record.url?scp=85100996084&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciimmunol.abd3489
DO - https://doi.org/10.1126/sciimmunol.abd3489
M3 - Article
C2 - 33514640
SN - 2470-9468
VL - 6
JO - Science immunology
JF - Science immunology
IS - 55
M1 - eabd3489
ER -