Basal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extent

TitleBasal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extent
Publication TypeJournal Article
Year of Publication2014
AuthorsFreeman CM, McCubbrey AL, Crudgington S, Nelson J, Martinez FJ, Han MLK, Washko GR, Chensue SW, Arenberg DA, Meldrum CA, McCloskey L, Curtis JL
JournalPLoS One
Volume9
Issue5
Paginatione96421
Date Published2014
ISSN1932-6203
KeywordsAged, CD4-Positive T-Lymphocytes, Cytokines, Female, Gene Expression, Humans, Lung, Lymphocyte Activation, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Severity of Illness Index
Abstract

UNLABELLED: Lung CD4+ T cells accumulate as chronic obstructive pulmonary disease (COPD) progresses, but their role in pathogenesis remains controversial. To address this controversy, we studied lung tissue from 53 subjects undergoing clinically-indicated resections, lung volume reduction, or transplant. Viable single-cell suspensions were analyzed by flow cytometry or underwent CD4+ T cell isolation, followed either by stimulation with anti-CD3 and cytokine/chemokine measurement, or by real-time PCR analysis. In lung CD4+ T cells of most COPD subjects, relative to lung CD4+ T cells in smokers with normal spirometry: (a) stimulation induced minimal IFN-γ or other inflammatory mediators, but many subjects produced more CCL2; (b) the T effector memory subset was less uniformly predominant, without correlation with decreased IFN-γ production. Analysis of unstimulated lung CD4+ T cells of all subjects identified a molecular phenotype, mainly in COPD, characterized by markedly reduced mRNA transcripts for the transcription factors controlling TH1, TH2, TH17 and FOXP3+ T regulatory subsets and their signature cytokines. This mRNA-defined CD4+ T cell phenotype did not result from global inability to elaborate mRNA; increased transcripts for inhibitory CD28 family members or markers of anergy; or reduced telomerase length. As a group, these subjects had significantly worse spirometry, but not DLCO, relative to subjects whose lung CD4+ T cells expressed a variety of transcripts. Analysis of mRNA transcripts of unstimulated lung CD4+ T cell among all subjects identified two distinct molecular correlates of classical COPD clinical phenotypes: basal IL-10 transcripts correlated independently and inversely with emphysema extent (but not spirometry); by contrast, unstimulated IFN-γ transcripts correlated independently and inversely with reduced spirometry (but not reduced DLCO or emphysema extent). Aberrant lung CD4+ T cells polarization appears to be common in advanced COPD, but also exists in some smokers with normal spirometry, and may contribute to development and progression of specific COPD phenotypes.

TRIAL REGISTRATION: ClinicalTrials.gov as NCT00281229.

DOI10.1371/journal.pone.0096421
Alternate JournalPLoS ONE
PubMed ID24805101
PubMed Central IDPMC4013040
Grant ListK23 HL093351 / HL / NHLBI NIH HHS / United States
K24 HL04212 / HL / NHLBI NIH HHS / United States
N01 HR046162 / HR / NHLBI NIH HHS / United States
P30 CA46952 / CA / NCI NIH HHS / United States
R01 HL082480 / HL / NHLBI NIH HHS / United States
R01 HL082480 / HL / NHLBI NIH HHS / United States
T32 AI007413 / AI / NIAID NIH HHS / United States
T32 AI007413 / AI / NIAID NIH HHS / United States
UL1 RR024986 / RR / NCRR NIH HHS / United States