title: Autoreactive T Cells in Human Smokers is Predictive of Clinical Outcome.
abstract: Cross-sectional studies have suggested a role for activation of adaptive immunity in smokers with emphysema, but the clinical application of these findings has not been explored. Here we examined the utility of detecting autoreactive T cells as a screening tool for emphysema in an at-risk population of smokers. We followed 156 former and current (ever)-smokers for 2 years to assess whether peripheral blood CD4 T cell cytokine responses to lung elastin fragments (EFs) could discriminate between those with and without emphysema, and to evaluate the relevance of autoreactive T cells to predict changes during follow-up in lung physiological parameters. Volunteers underwent baseline complete phenotypic assessment with pulmonary function tests, quantitative chest CT, yearly 6-min walk distance (6MWD) testing, and annual measurement of CD4 T cell cytokine responses to EFs. The areas under the receiver operating characteristic curve to predict emphysema for interferon gamma (IFN-γ), and interleukin 6 (IL-6) responses to EFs were 0.81 (95% CI of 0.74-0.88) and 0.79 (95% CI of 0.72-0.86) respectively. We developed a dual cytokine enzyme-linked immunocell spot assay, the γ-6 Spot, using CD4 T cell IFN-γ and IL-6 responses and found that it discriminated emphysema with 90% sensitivity. After adjusting for potential confounders, the presence of autoreactive T cells was predictive of a decrease in 6MWD over 2 years (decline in 6MWD, -19 m per fold change in IFN-γ; P = 0.026, and -26 m per fold change in IL-6; P = 0.003). In support of the human association studies, we cloned CD4 T cells with characteristic T helper (Th)1 and Th17 responses to EFs in the peripheral blood of ever-smokers with emphysema, confirming antigenicity of lung elastin in this population. These findings collectively suggest that the EF-specific autoreactive CD4 T cell assay, γ-6 Spot, could provide a non-invasive diagnostic tool with potential application to large-scale screening to discriminate emphysema in ever-smokers, and predict early relevant physiological outcomes in those at risk.
authors.affiliation: Baylor College of Medicine Houston, TX, USA.
authors.forename: Chuang
authors.initials: C
authors.lastname: Xu
authors.forename: Sean
authors.initials: S
authors.lastname: Hesselbacher
authors.forename: Chu-Lin
authors.initials: CL
authors.lastname: Tsai
authors.forename: Ming
authors.initials: M
authors.lastname: Shan
authors.forename: Margaret
authors.initials: M
authors.lastname: Spitz
authors.forename: Michael
authors.initials: M
authors.lastname: Scheurer
authors.forename: Luz
authors.initials: L
authors.lastname: Roberts
authors.forename: Sarah
authors.initials: S
authors.lastname: Perusich
authors.forename: Nazanin
authors.initials: N
authors.lastname: Zarinkamar
authors.forename: Harvey
authors.initials: H
authors.lastname: Coxson
authors.forename: Natasha
authors.initials: N
authors.lastname: Krowchuk
authors.forename: David B
authors.initials: DB
authors.lastname: Corry
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand