A neonatal bias towards CX3CR1 ++ memory CD8+ T cells is associated with impaired control of Cytomegalovirus in early life 2232221

Abstract

Abstract Introduction Congenital cytomegalovirus (CMV) is a leading cause of hearing loss and neurological deficits. A risk factor for congenital CMV is primary exposure of pregnant individuals to the virus in bodily fluids. CMV infected adults stopped shedding virus in bodily fluids within ∼6 months of seroconversion compared to children who continued shedding virus in bodily fluids for ∼4 years after seroconversion. Methods Here we sought to replicate this phenomenon in a mouse model with the Murine strain of CMV by infecting neonatal and adult mice. We then examined the cellular intrinsic differences between neonatal and adult CD8+ T cells by performing adoptive co-transfers into congenic hosts. Our group utilized spectral flow cytometry, bulk RNA-sequencing and in vivo animal imaging to better characterize this phenomenon. Results Infected neonatal mice continued to shed virus for >12 weeks post-infection, while infected adult mice stopped shedding at 4 weeks post-infection. Both adult and neonatal CD8+ T cells upregulated CX3CR1 in response to CMV infection, however, neonatal CD8+ T cells terminally differentiated into a unique CX3CR1 ++ population that was functionally impaired in the ability to make IFNγ. This ‘dysfunctional’ CX3CR1 ++ population in neonates was specific to CMV, as neonatal CD8+ T cells in response to vaccinia made robust IFNγ. Higher expression of CX3CR1 on neonatal CD8+ T cells had a physiological role by promoting the T cells to stay vascularized, while adult CD8+ T cells were readily able to disseminate into the extravascular space of tissues. Conclusion This work provides the first identified mechanism that explains why the host immune response of neonates fails to control CMV viral replication and shedding. Funding Source American Association of Immunologist (AAI) — Postdoctoral Intersect Fellowship for Computational Scientists and Immunologist Topic Categories Viral Immunology (VIR)