title: Cytotoxic potential of lung CD8(+) T cells increases with chronic obstructive pulmonary disease severity and with in vitro stimulation by IL-18 or IL-15.
abstract: Lung CD8(+) T cells might contribute to progression of chronic obstructive pulmonary disease (COPD) indirectly via IFN-gamma production or directly via cytolysis, but evidence for either mechanism is largely circumstantial. To gain insights into these potential mechanisms, we analyzed clinically indicated lung resections from three human cohorts, correlating findings with spirometrically defined disease severity. Expression by lung CD8(+) T cells of IL-18R and CD69 correlated with severity, as did mRNA transcripts for perforin and granzyme B, but not Fas ligand. These correlations persisted after correction for age, smoking history, presence of lung cancer, recent respiratory infection, or inhaled corticosteroid use. Analysis of transcripts for killer cell lectin-like receptor G1, IL-7R, and CD57 implied that lung CD8(+) T cells in COPD do not belong to the terminally differentiated effector populations associated with chronic infections or extreme age. In vitro stimulation of lung CD8(+) T cells with IL-18 plus IL-12 markedly increased production of IFN-gamma and TNF-alpha, whereas IL-15 stimulation induced increased intracellular perforin expression. Both IL-15 and IL-18 protein expression could be measured in whole lung tissue homogenates, but neither correlated in concentration with spirometric severity. Although lung CD8(+) T cell expression of mRNA for both T-box transcription factor expressed in T cells and GATA-binding protein 3 (but not retinoic acid receptor-related orphan receptor gamma or alpha) increased with spirometric severity, stimulation of lung CD8(+) T cells via CD3epsilon-induced secretion of IFN-gamma, TNF-alpha, and GM-CSF, but not IL-5, IL-13, and IL-17A. These findings suggest that the production of proinflammatory cytokines and cytotoxic molecules by lung-resident CD8(+) T cells contributes to COPD pathogenesis.
authors.affiliation: Pulmonary and Critical Care Medicine Section, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, 48105-2303, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freeman
authors.forename: MeiLan K
authors.initials: MK
authors.lastname: Han
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.forename: Susan
authors.initials: S
authors.lastname: Murray
authors.forename: Lyrica X
authors.initials: LX
authors.lastname: Liu
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Chensue
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Polak
authors.forename: Joanne
authors.initials: J
authors.lastname: Sonstein
authors.forename: Jill C
authors.initials: JC
authors.lastname: Todt
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ames
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Arenberg
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Meldrum
authors.forename: Christi
authors.initials: C
authors.lastname: Getty
authors.forename: Lisa
authors.initials: L
authors.lastname: McCloskey
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D005541:Forced Expiratory Volume; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology*; D037181:Lectins, C-Type / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D012129:Respiratory Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D019409:Interleukin-15; D020382:Interleukin-18; D037181:Lectins, C-Type; D012333:RNA, Messenger; D000099192:CD69 Antigens