Human cytomegalovirus (HCMV) infection of the neonatal CNS results in long-term neurologic sequelae. To define the pathogenesis of fetal HCMV CNS infections, we investigated mechanisms of virus clearance from the CNS of neonatal Balb/c mice infected with murine CMV (MCMV). Virus titers peaked in the CNS between post-natal (PN) days 10–14 and infectious virus was undetectable by PN day 21. Congruent with virus clearance was the recruitment of CD8+ T-cells into the CNS. Depletion of CD8+ T cells resulted in death by postnatal day 15 in MCMV infected animals and increased viral loads in the liver, spleen and the CNS suggesting an important role for these cells in the control of MCMV replication in the newborn brain. Examination of brain mononuclear cells revealed that CD8+ T-cell infiltrates expressed high levels of CD69, CD44 and CD49d. IE1168 specific CD8+ T-cells accumulated in the CNS and produced IFN-γ and TNF-α but not IL-2 following peptide stimulation. Moreover, adoptive transfer of brain mononuclear cells resulted in decreased virus burden in immunodepleted MCMV infected syngeneic mice. Depletion of the CD8+ cell population following transfer eliminated control of virus replication. In summary, these results show that functionally mature virus specific CD8+ T-cells are recruited to the CNS in mice infected with MCMV as neonates.
Memory T cells form a highly specific defense layer against reinfection with previously encountered pathogens. In addition, memory T cells provide protection against pathogens that are similar, but not identical to the original infectious agent. This is because each T cell response harbors multiple clones with slightly different affinities, thereby creating T cell memory with a certain degree of diversity. Currently, the mechanisms that control size, diversity, and cross-reactivity of the memory T cell pool are incompletely defined. Previously, we established a role for apoptosis, mediated by the BH3-only protein Noxa, in controlling diversity of the effector T cell population. This function might positively or negatively impact T cell memory in terms of function, pool size, and cross-reactivity during recall responses. Therefore, we investigated the role of Noxa in T cell memory during acute and chronic infections. Upon influenza infection, Noxa−/− mice generate a memory compartment of increased size and clonal diversity. Reinfection resulted in an increased recall response, whereas cross-reactive responses were impaired. Chronic infection of Noxa−/− mice with mouse CMV resulted in enhanced memory cell inflation, but no obvious pathology. In contrast, in a model of continuous, high-level T cell activation, reduced apoptosis of activated T cells rapidly led to severe organ pathology and premature death in Noxa-deficient mice. These results establish Noxa as an important regulator of the number of memory cells formed during infection. Chronic immune activation in the absence of Noxa leads to excessive accumulation of primed cells, which may result in severe pathology.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.