Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs.
Innate lymphoid cells (ILCs) are critical mediators of mucosal immunity, and group 1 ILCs (ILC1 cells) and group 3 ILCs (ILC3 cells) have been shown to be functionally plastic. Here we found that group 2 ILCs (ILC2 cells) also exhibited phenotypic plasticity in response to infectious or noxious agents, characterized by substantially lower expression of the transcription factor GATA-3 and a concomitant switch to being ILC1 cells that produced interferon-γ (IFN-γ). Interleukin 12 (IL-12) and IL-18 regulated this conversion, and during viral infection, ILC2 cells clustered within inflamed areas and acquired an ILC1-like phenotype. Mechanistically, these ILC1 cells augmented virus-induced inflammation in a manner dependent on the transcription factor T-bet. Notably, IL-12 converted human ILC2 cells into ILC1 cells, and the frequency of ILC1 cells in patients with chronic obstructive pulmonary disease (COPD) correlated with disease severity and susceptibility to exacerbations. Thus, functional plasticity of ILC2 cells exacerbates anti-viral immunity, which may have adverse consequences in respiratory diseases such as COPD.
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, Maryland, USA.
Jonathan S
JS
Silver
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, Maryland, USA.
Jennifer
J
Kearley
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, Maryland, USA.
Alan M
AM
Copenhaver
Department of Experimental Medical Science, Lund University, Lund, Sweden.|Medetect, Lund, Sweden.
Caroline
C
Sanden
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Michiko
M
Mori
Non-Clinical Biostatistics, Department of Translational Sciences, MedImmune, Gaithersburg, Maryland, USA.
Li
L
Yu
University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
Gretchen Harms
GH
Pritchard
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, Maryland, USA.
Aaron A
AA
Berlin
University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
Christopher A
CA
Hunter
National Jewish Health, Denver, Colorado, USA.
Russell
R
Bowler
Department of Experimental Medical Science, Lund University, Lund, Sweden.|Medetect, Lund, Sweden.
Jonas S
JS
Erjefalt
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, Maryland, USA.
Roland
R
Kolbeck
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, Maryland, USA.
Alison A
AA
Humbles
D000368:Aged; D000818:Animals; D002454:Cell Differentiation; D000066670:Cell Plasticity / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006192:Haemophilus Infections / Q000276:immunology*; D006193:Haemophilus influenzae / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D009980:Influenza A virus / Q000276:immunology*; D008168:Lung / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology*; D012907:Smoking / Q000009:adverse effects; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D000098815:T-bet Transcription Factor
D016207:Cytokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D018836:Inflammation Mediators; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor