CD40-CD40 Ligand Interactions Promote Trafficking of CD8 ⁺ T Cells into the Brain and Protection against West Nile Virus Encephalitis

Abstract

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.

CD22 Is Required for Protection against West Nile Virus Infection

“…Thus, the CD22-dependent defect in migration of cells into the CNS predominantly affects T cells. It has been established that infiltrating T cells are important for controlling virus replication in the CNS and, ultimately, survival of the host from succumbing to encephalitic disease (43,44). Thus, the diminished number of WNV-specific CD8 ϩ T cells in the spleens of Cd22 Ϫ/Ϫ mice along with the decreased CD8 ϩ T cell infiltrates and inability to control viral replication in the brain likely accounts for Cd22 Ϫ/Ϫ mice succumbing to disease after WNV infection.…”

Early B-Cell Activation after West Nile Virus Infection Requires Alpha/Beta Interferon but Not Antigen Receptor Signaling

“…Maturation of surface IgM ϩ naive B cells into high-affinity antigen-specific B cells (34) usually requires antigen stimulation in the context of costimulatory signals (e.g., CD40 or complement receptor 2) and CD4 ϩ T-cell help. Indeed, for WNV-NY infection, accumulation of antigen-specific IgG in serum was delayed and blunted in class II MHC Ϫ/Ϫ , CD4 Ϫ/Ϫ , and CD40 Ϫ/Ϫ mice (49,50). Given the phenotype of rapid B-cell activation in the draining LN, we questioned whether this translated directly into an antigen-specific IgM response.…”

Toll-Like Receptor 3 Has a Protective Role against West Nile Virus Infection

“…The levels of WNV-specific immunoglobulin M (IgM) and IgG were determined by using an ELISA against purified WNV E protein (10). Intracellular IFN-␥ staining was performed on day-7-infected splenocytes using a D b -restricted NS4B peptide restimulation assay as previously described (41,53). Samples were processed by two-color flow cytometry.…”

“…Quantification of infiltrating CNS lymphocytes was performed by flow cytometry as previously described (50,53). Briefly, wild-type and TLR3…”