Autoreactive T cells in human smokers is predictive of clinical outcome

Chuang Xu, Sean Hesselbacher, Chu Lin Tsai, Ming Shan, Margaret Spitz, Michael Scheurer, Luz Roberts, Sarah Perusich, Nazanin Zarinkamar, Harvey Coxson, Natasha Krowchuk, David Corry, Farrah Kheradmand

Research output: Contribution to journalArticle

21 Scopus citations

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 phe-notypic assessment with pulmonary function tests, quantitative chest CT, yearly 6-min walk distance (6MWD) testing, and annual measurement of CD4T 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 CD4T cell IFN-γ and IL-6 responses and found that it discriminated emphysema with 90% sensitivity. After adjusting for potential confounders, the presence of autoreactiveT cells was predictive of a decrease in 6MWD over 2years (decline in 6MWD, -19m 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 CD4T cells with characteristicT 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.

Original languageEnglish (US)
Article number267
JournalFrontiers in immunology
Volume3
Issue numberAUG
DOIs
StatePublished - 2012

Keywords

  • Autoreactive T cells
  • Emphysema
  • Humans
  • Immuno-assays
  • T cell cloning
  • Tetramers
  • Th1
  • Th17

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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