4.5 Article

Metabolic and functional impairment of CD8+ T cells from the lungs of influenza-infected obese mice

期刊

JOURNAL OF LEUKOCYTE BIOLOGY
卷 111, 期 1, 页码 147-159

出版社

WILEY
DOI: 10.1002/JLB.4A0120-075RR

关键词

Immunity; Pulmonary; Effector

资金

  1. Cancer Center Core Support Grant [P30 CA016086]
  2. North Carolina Biotech Center Institutional Support Grant [2017-IDG-1025]
  3. National Institutes of Health [1UM2AI30836-01, R01AT008375, R01ES031378, P30DK056350]
  4. NIH National Research Service Award [T32-DK007686]
  5. National Science Foundation [1650116]
  6. Sanofi
  7. Division Of Graduate Education
  8. Direct For Education and Human Resources [1650116] Funding Source: National Science Foundation

向作者/读者索取更多资源

The study suggests that diet-induced obesity may increase influenza virus pathogenesis through CD8(+) T cell-mediated metabolic reprogramming and impaired effector CD8(+) T cell function.
Obesity is an independent risk factor for morbidity and mortality in response to influenza infection. However, the underlying mechanisms by which obesity impairs immunity are unclear. Herein, we investigated the effects of diet-induced obesity on pulmonary CD8(+) T cell metabolism, cytokine production, and transcriptome as a potential mechanism of impairment during influenza virus infection in mice. Male C57BL/6J lean and obese mice were infected with sub-lethal mouse-adapted A/PR/8/34 influenza virus, generating a pulmonary anti-viral and inflammatory response. Extracellular metabolic flux analyses revealed pulmonary CD8(+) T cells from obese mice, compared with lean controls, had suppressed oxidative and glycolytic metabolism at day 10 post-infection. Flow cytometry showed the impairment in pulmonary CD8(+) T cell metabolism with obesity was independent of changes in glucose or fatty acid uptake, but concomitant with decreased CD8(+)GrB(+)IFN gamma(+) populations. Notably, the percent of pulmonary effector CD8(+)GrB(+)IFN gamma(+) T cells at day 10 post-infection correlated positively with total CD8(+) basal extracellular acidification rate and basal oxygen consumption rate. Finally, next-generation RNA sequencing revealed complex and unique transcriptional regulation of sorted effector pulmonary CD8(+)CD44(+) T cells from obese mice compared to lean mice following influenza infection. Collectively, the data suggest diet-induced obesity increases influenza virus pathogenesis, in part, through CD8(+) T cell-mediated metabolic reprogramming and impaired effector CD8(+) T cell function.

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