Enhanced CD8 T-cell anti-viral function and clinical disease in B7-H1-deficient mice requires CD4 T cells during encephalomyelitis

Journal of Neuroinflammation

Cornelia C Bergmann¹  David R Hinton²  Stephen A Stohlman¹  Timothy W Phares¹ 

[1] Departments of Neurosciences NC30, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA;Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

关键词: Axonal damage;    Inflammation;    Gliatropic coronavirus;    CD4⁺ and CD8⁺ T cells;    Encephalomyelitis;    Central nervous system;   

Others  :  1160119
DOI  :  10.1186/1742-2094-9-269

 received in 2012-07-31, accepted in 2012-12-03,  发布年份 2012

【 摘 要 】

Background

Anti-viral CD8 T-cell activity is enhanced and prolonged by CD4 T-cell-mediated help, but negatively regulated by inhibitory B7-H1 interactions. During viral encephalomyelitis, the absence of CD4 T cells decreases CD8 T cell activity and impedes viral control in the central nervous system (CNS). By contrast, the absence of B7-H1 enhances CD8 T-cell function and accelerates viral control, but increases morbidity. However, the relative contribution of CD4 T cells to CD8 function in the CNS, in the absence of B7-H1, remains unclear.

Methods

Wild-type (WT) and B7-H1^−/− mice were infected with a gliatropic coronavirus and CD4 T cells depleted to specifically block T helper function in the CNS. Flow cytometry and gene expression analysis of purified T-cell populations from lymph nodes and the CNS was used to directly monitor ex vivo T-cell effector function. The biological affects of altered T-cell responses were evaluated by analysis of viral control and spinal-cord pathology.

Results

Increased anti-viral activity by CD8 T cells in the CNS of B7-H1^−/− mice was lost upon depletion of CD4 T cells; however, despite concomitant loss of viral control, the clinical disease was less severe. CD4 depletion in B7-H1^−/− mice also decreased inducible nitric oxide synthase expression by microglia and macrophages, consistent with decreased microglia/macrophage activation and reduced interferon (IFN)-γ. Enhanced production of IFN-γ, interleukin (IL)-10 and IL-21 mRNA was seen in CD4 T cells from infected B7-H1^−/− compared with WT mice, suggesting that over-activated CD4 T cells primarily contribute to the increased pathology.

Conclusions

The local requirement of CD4 T-cell help for CD8 T-cell function is not overcome if B7-H1 inhibitory signals are lost. Moreover, the increased effector activity by CD8 T cells in the CNS of B7-H1^−/− mice is attributable not only to the absence of B7-H1 upregulation on major histocompatibility complex class I-presenting resident target cells, but also to enhanced local CD4 T-cell function. B7-H1-mediated restraint of CD4 T-cell activity is thus crucial to dampen both CD8 T-cell function and microglia/macrophage activation, thereby providing protection from T-cell-mediated bystander damage.

【 授权许可】

   
2012 Phares et al.; licensee BioMed Central Ltd.

【 图 表 】

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