CD40-CD40 ligand interactions promote trafficking of CD8+ T cells into the brain and protection against West Nile virus encephalitis.
Recent studies have established a protective role for T cells during primary West Nile virus (WNV) infection. Binding of CD40 by CD40 ligand (CD40L) on activated CD4+ T cells provides an important costimulatory signal for immunoglobulin class switching, antibody affinity maturation, and priming of CD8+ T-cell responses. We examined here the function of CD40-dependent interactions in limiting primary WNV infection. Compared to congenic wild-type mice, CD40(-/-) mice uniformly succumbed to WNV infection. Although CD40(-/-) mice produced low levels of WNV-specific immunoglobulin M (IgM) and IgG, viral clearance from the spleen and serum was not altered, and CD8+ T-cell priming in peripheral lymphoid tissues was normal. Unexpectedly, CD8+ T-cell trafficking to the central nervous system (CNS) was markedly impaired in CD40(-/-) mice, and this correlated with elevated WNV titers in the CNS and death. In the brains of CD40(-/-) mice, T cells were retained in the perivascular space and did not migrate into the parenchyma, the predominant site of WNV infection. In contrast, in wild-type mice, T cells trafficked to the site of infection in neurons. Beside its role in maturation of antibody responses, our experiments suggest a novel function of CD40-CD40L interactions: to facilitate T-cell migration across the blood-brain barrier to control WNV infection.
Sitati
Elizabeth
E
Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
McCandless
Erin E
EE
Klein
Robyn S
RS
Diamond
Michael S
MS
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000915:Antibody Affinity / Q000276:immunology; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000473:pathology / Q000821:virology; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000172:deficiency / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology*; D006224:Cricetinae; D017578:Immunoglobulin Class Switching; D007075:Immunoglobulin M / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000276:immunology / Q000473:pathology / Q000821:virology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014901:West Nile Fever / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014902:West Nile virus / Q000276:immunology*
D000914:Antibodies, Viral; D019013:CD40 Antigens; D007075:Immunoglobulin M; D023201:CD40 Ligand