title: Basal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extent.
abstract: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov as NCT00281229.
authors.affiliation: Research Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, United States of America; Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: McCubbrey
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Crudgington
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Nelson
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
authors.forename: MeiLan K
authors.initials: MK
authors.lastname: Han
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham & Womans Hospital and Harvard University, Boston, Massachusetts, United States of America.
authors.forename: George R
authors.initials: GR
authors.lastname: Washko
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, United States of America; Pathology and Laboratory Medicine Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, United States of America; Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Chensue
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Arenberg
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Meldrum
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: McCloskey
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America; Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, United States of America; Pulmonary and Critical Care Medicine Section, Medicine Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, United States of America.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
mesh_terms: D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D011656:Pulmonary Emphysema / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: D016207:Cytokines