title: Enhanced CD8 T-cell anti-viral function and clinical disease in B7-H1-deficient mice requires CD4 T cells during encephalomyelitis.
abstract: 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.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000998:Antiviral Agents / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen / Q000172:deficiency*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology*; D016207:Cytokines; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000209:etiology / Q000235:genetics / Q000473:pathology; D005434:Flow Cytometry; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D006517:Murine hepatitis virus / Q000472:pathogenicity; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D000906:Antibodies; D000998:Antiviral Agents; D060890:B7-H1 Antigen; D015704:CD4 Antigens; C498919:Cd274 protein, mouse; D016207:Cytokines