Chronic thoracic spinal cord injury impairs CD8+ T-cell function by up-regulating programmed cell death-1 expression

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• 作者：Ji Zha (12)
  Annalise Smith (13)
  Samita Andreansky (13) (14)
  Valerie Bracchi-Ricard (12)
  John R Bethea (15)
  
  12. The Miami Project to Cure Paralysis ; Department of Neurosurgery ; Miller School of Medicine ; University of Miami ; Miami ; FL ; 33136 ; USA
  13. Department of Microbiology and Immunology ; Miller School of Medicine ; University of Miami ; Miami ; FL ; 33136 ; USA
  14. Department of Pediatrics and Medicine ; Miller School of Medicine ; University of Miami ; Miami ; FL ; 33136 ; USA
  15. Department of Biology ; Drexel University ; Philadelphia ; PA ; 19104 ; USA
  
• 关键词：Spinal cord injury ; T ; cell exhaustion ; PD ; 1 ; Norepinephrine
• 刊名：Journal of Neuroinflammation
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：11
• 期：1
• 全文大小：920 KB
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• 刊物主题：Neurosciences; Neurology; Neurobiology; Immunology;
• 出版者：BioMed Central
• ISSN：1742-2094

文摘

Background Chronic spinal cord injury (SCI) induces immune depression in patients, which contributes to their higher risk of developing infections. While defects in humoral immunity have been reported, complications in T-cell immunity during the chronic phase of SCI have not yet been explored. Methods To assess the impact of chronic SCI on peripheral T-cell number and function we used a mouse model of severe spinal cord contusion at thoracic level T9 and performed flow cytometry analysis on the spleen for T-cell markers along with intracellular cytokine staining. Furthermore we identified alterations in sympathetic activity in the spleen of chronic SCI mice by measuring splenic levels of tyrosine hydroxylase (TH) and norepinephrine (NE). To gain insight into the neurogenic mechanism leading to T-cell dysfunction we performed in vitro NE stimulation of T-cells followed by flow cytometry analysis for T-cell exhaustion marker. Results Chronic SCI impaired both CD4+ and CD8+ T-cell cytokine production. The observed T-cell dysfunction correlated with increased expression of programmed cell death 1 (PD-1) exhaustion marker on these cells. Blocking PD-1 signaling in vitro restored the CD8+ T-cell functional defect. In addition, we showed that chronic SCI mice had higher levels of splenic NE, which contributed to the T-cell exhaustion phenotype, as PD-1 expression on both CD4+ and CD8+ T-cells was up-regulated following sustained exposure to NE in vitro. Conclusions These studies indicate that alteration of sympathetic activity following chronic SCI induces CD8+ T-cell exhaustion, which in turn impairs T-cell function and contributes to immune depression. Inhibition of the exhaustion pathway should be considered as a new therapeutic strategy for chronic SCI-induced immune depression.