Brain-resident memory CD8+ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

Abstract

Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with mouse cytomegalovirus (MCMV) intraperitoneally is a well-established model of congenital human cytomegalovirus infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here, we used this model to investigate the role, dynamics, and phenotype of CD8⁺ T cells in the brain following infection of newborn mice. We show that CD8⁺ T cells infiltrate the brain and form a pool of tissue-resident memory T cells (T_RM cells) that persist for lifetime. Adoptively transferred virus-specific CD8⁺ T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology, and remain in the brain as T_RM cells. Brain CD8⁺ T_RM cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8⁺ T_RM cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain.

Keywords: Brain pathology; Congenital CMV infection; Microglia; Mouse cytomegalovirus; Tissue-resident memory T cells.