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 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 cells. Brain CD8 T cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8 T cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain.

Tissue-resident memory T cells populate the human brain

“…This profound inflammatory potential of brain CD8 + is highlighted by the substantial production of IFN-γ, TNF-α, and even GM-CSF upon activation. The polyfunctional inflammatory cytokine profile of human T RM cells was previously also observed for lung CD103 + and CD103 − T RM cells 44 , and mouse cytomegalovirus-specific and Toxoplasma gondii -specific CD8 + brain T RM cells also produced IFN-γ and TNF-α 45 , 46 . GM-CSF may be of particular relevance to T RM cells residing in the white matter, since microglia express the GM-CSF-receptor complex and are readily activated by GM-CSF 47 .…”

Tissue-resident lymphocytes: from adaptive to innate immunity

“…61 Accumulation of T RM cells has been established in the brain of newborn mice after intraperitoneal mouse cytomegalovirus (MCMV) infection, which provides protection against primary MCMV infection and reduce brain pathology. 83 Depletion of these cells results in virus reactivation and enhanced inflammation in the brain. 83 Models using LCMV have revealed the protective role of brain-resident T RM cells in restricting viral infection in the CNS.…”

“…83 Depletion of these cells results in virus reactivation and enhanced inflammation in the brain. 83 Models using LCMV have revealed the protective role of brain-resident T RM cells in restricting viral infection in the CNS. 84 T RM cells are generated and maintained in the CNS tissues after intracranial infection with TMEV, and a lack of this cell population results in compromised control of heterologous virus rechallenge.…”

Environmental Signals on Microglial Function during Brain Development, Neuroplasticity, and Disease

“…In addition to ZIKV, other viruses such as cytomegalovirus (CMV) and Rubella also cross the placental barrier and/or BBB and reach the CNS [89]. CMV infection of newborn mice induces a strong inflammatory response in the brain, characterized by microglial activation, recruitment of peripheral immune cells, and the expression of pro-inflammatory cytokines [91]. Thus, inflammation induced by viral infection is more responsible for neurodevelopmental abnormalities than the direct cytopathic effect of the virus on infected cells [92].…”