PD1⁺CCR2⁺CD8⁺ T Cells Infiltrate the Central Nervous System during Acute Japanese Encephalitis Virus Infection

Abstract

Japanese encephalitis (JE) is a viral encephalitis disease caused by Japanese encephalitis virus (JEV) infection. Uncontrolled inflammatory responses in the central nervous system (CNS) are a hallmark of severe JE. Although the CCR2–CCL2 axis is important for monocytes trafficking during JEV infection, little is known about its role in CNS trafficking of CD8⁺ T cells. Here, we characterized a mouse model of JEV infection, induced via intravenous injection (i.v.) and delineated the chemokines and infiltrating peripheral immune cells in the brains of infected mice. The CNS expression of chemokines, Ccl2, Ccl3, and Ccl5, and their receptors, Ccr2 or Ccr5, was significantly up-regulated after JEV infection and was associated with the degree of JE pathogenesis. Moreover, JEV infection resulted in the migration of a large number of CD8⁺ T cells into the CNS. In the brains of JEV-infected mice, infiltrating CD8⁺ T cells expressed CCR2 and CCR5 and were found to comprise mainly effector T cells (CD44⁺CD62L⁻). JEV infection dramatically enhanced the expression of programmed death 1 (PD-1) on infiltrating CD8⁺ T cells in the brain, as compared to that on peripheral CD8⁺ T cells in the spleen. This effect was more pronounced on infiltrating CCR2⁺CD8⁺ T cells than on CCR2⁻CD8⁺ T cells. In conclusion, we identified a new subset of CD8⁺ T cells (PD1⁺CCR2⁺CD8⁺ T cells) present in the CNS of mice during acute JEV infection. These CD8⁺ T cells might play a role in JE pathogenesis.