Limited protection against early-life lung murine cytomegalovirus infection results from deficiency of cytotoxic CD8 T cells

Abstract

Differential antiviral T cell immunity in early life impacts the clinical outcome of Cytomegalovirus (CMV) infection, but the underlying mechanisms are not well understood. T cells are known to be involved in protection from CMV disease. To further elucidate these mechanisms, we used a model of respiratory murine CMV (MCMV) infection and adoptive T cell transfers to characterize MCMV-specific T cell responses in early life. We analyzed the effector T cell differentiation using single-cell RNA sequencing and assessed the local pulmonary cytokine milieu. We found delayed enrichment of early-life murine MCMV-specific CD8 T cells due to a general deficiency of αβ T cells. Adoptive transfer of naïve adult T cells into neonates did not protect from lung MCMV infection due to generation of non-cytotoxic CD8 effector T cells. Furthermore, key cytokines required for effective CD8 T cell priming were absent in early life. Supplementation with these cytokines enhanced infection control by transferred adult T cells. The effector function of adult-primed T cells was not disrupted in neonates. Together, this study suggests defective CD8 T cell priming in neonates as a factor explaining the higher risk for MCMV lung disease in the early-life phase.