In utero human cytomegalovirus infection expands NK cell-like FcγRIII-expressing CD8+ T cells that mediate antibody-dependent functions

Human cytomegalovirus (HCMV) profoundly modulates host T and natural killer (NK) cells across the lifespan, expanding unique effector cells bridging innate and adaptive immunity. Though HCMV is the most common congenital infection worldwide, how this ubiquitous herpesvirus impacts developing fetal T and NK cells remains unclear. Using computational flow cytometry and transcriptome profiling of cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify major shifts in fetal cellular immunity marked by an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells (FcRT) following HCMV exposure in utero. FcRT cells from cCMV-infected neonates express a cytotoxic NK cell-like transcriptome and mediate antigen-specific antibody-dependent functions including degranulation and IFNγ production, the hallmarks of NK cell antibody-dependent cellular cytotoxicity (ADCC). FcRT cells may represent a previously unappreciated effector population with innate-like functions that could be harnessed for maternal-infant vaccination strategies and antibody-based therapeutics in early life. ![Figure][1] ### Competing Interest Statement The authors of this manuscript have the following financial conflict of interest to disclose: JK is a consultant for Matrix Capital Management Fund, the medical director of the Carolinas Cord Blood Bank, the medical director of the Cryo-Cell Cord Blood Bank, and receives royalties from a licensing agreement between Duke and Cryo-Cell and Duke and Sinocell for data and regulatory packages regarding manufacturing and therapeutic use of cord blood and cord tissue cells in patients with cerebral palsy, hypoxic ischemic encephalopathy, stroke, and autism. SRP is a consultant for Moderna, Merck, Pfizer, GSK, Dynavax, and Hoopika CMV vaccine programs and leads sponsored research programs with Moderna, Merck, and Dynavax. She also serves on the board of the National CMV Foundation and as an educator on CMV for Medscape. KMW has a sponsored research project from Moderna on immune correlates of congenital CMV infection. The other authors have declared that no other conflict of interest. ### Funding Statement This project was supported by NIH NCI 1R21CA242439-01 Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life ALL Development (KMW, SRP), NIH NIAID 1R01AI173333 Identifying and modeling immune correlates of protection against congenital CMV transmission after primary maternal infection (SRP), NIH NIAID R01AI145828 Innate immune signaling in placental antiviral defenses (CBC), the Triangle Center for Evolutionary Medicine (TriCEM) graduate student research award Human cytomegalovirus and host B cell evolution across the lifespan to ECS and the Translating Duke Health Childrens Health and Discovery Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval was obtained from the Duke University School of Medicine Institutional Review Board (Pro00089256) to use deidentified clinical data and biospecimens provided by the CCBB. No patients were prospectively recruited for this study, and all samples were acquired retrospectively from the CCBB biorepository from donors who had previously provided written consent for banked biospecimens to be used for research. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: pending:yes