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

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. © 2012 phares et al.; licensee biomed central ltd.