viruses Article Characterization of Adaptive-like γδ T Cells in Ugandan Infants during Primary Cytomegalovirus Infection Jessica Tuengel 1 , Sanya Ranchal 1 , Alexandra Maslova 2 , Gurpreet Aulakh 1 , Maria Papadopoulou 3,4,5 , Sibyl Drissler 6 , Bing Cai 1 , Cetare Mohsenzadeh-Green 1 , Hugo Soudeyns 7,8 , Sara Mostafavi 1,2 , Peter van den Elzen 1 , David Vermijlen 3,4,5 , Laura Cook 1,9 and Soren Gantt 7,8, *   Citation: Tuengel, J.; Ranchal, S.; Maslova, A.; Aulakh, G.; Papadopoulou, M.; Drissler, S.; Cai, B.; Mohsenzadeh-Green, C.; Soudeyns, H.; Mostafavi, S.; et al. Characterization of Adaptive-like γδ T Cells in Ugandan Infants during Primary Cytomegalovirus Infection. Viruses 2021, 13, 1987. https:// doi.org/10.3390/v13101987 Academic Editor: Graciela Andrei Received: 10 July 2021 Accepted: 27 September 2021 Published: 3 October 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; jessicaharli@gmail.com (J.T.); sranchal@student.ubc.ca (S.R.); gsaulakh@alumni.ubc.ca (G.A.); caibing@bcchr.ubc.ca (B.C.); cetarehmg@gmail.com (C.M.-G.); saram@stat.ubc.ca (S.M.); pvde@mail.ubc.ca (P.v.d.E.); l.cook@unimelb.edu.au (L.C.) 2 Department of Bioinformatics, University of British Columbia, Vancouver, BC V5T 4S6, Canada; sasha113@gmail.com 3 Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium; mpapadop@ulb.ac.be (M.P.); dvermijl@ulb.ac.be (D.V.) 4 Institute for Medical Immunology, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium 5 ULB Center for Research in Immunology, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium 6 Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; sdrissler@bccrc.ca 7 Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC H3C 3J7, Canada; hugo.soudeyns@umontreal.ca 8 CHU Sainte-Justine Research Centre, Montréal, QC H3T 1C5, Canada 9 Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia * Correspondence: soren.gantt@umontreal.ca Abstract: Gamma-delta (γδ) T cells are unconventional T cells that help control cytomegalovirus (CMV) infection in adults. γδ T cells develop early in gestation, and a fetal public γδ T cell receptor (TCR) clonotype is detected in congenital CMV infections. However, age-dependent γδ T cell responses to primary CMV infection are not well-understood. Flow cytometry and TCR sequencing was used to comprehensively characterize γδ T cell responses to CMV infection in a cohort of 32 infants followed prospectively from birth. Peripheral blood γδ T cell frequencies increased during infancy, and were higher among CMV-infected infants relative to uninfected. Clustering analyses revealed associations between CMV infection and activation marker expression on adaptive-like Vδ1 and Vδ3, but not innate-like Vγ9Vδ2 γδ T cell subsets. Frequencies of NKG2C + CD57 + γδ T cells were temporally associated with the quantity of CMV shed in saliva by infants with primary infection. The public γδ TCR clonotype was only detected in CMV-infected infants <120 days old and at lower frequencies than previously described in fetal infections. Our findings support the notion that CMV infection drives age-dependent expansions of specific γδ T cell populations, and provide insight for novel strategies to prevent CMV transmission and disease. Keywords: CMV; gamma delta T cell; gammadelta; Vδ1; Vδ3; Vγ8; Vγ9 neg Vδ2; cCMV; NKG2C; immune ontogeny 1. Introduction Cytomegalovirus (CMV) infects most of the world’s population, beginning in early childhood [1]. Postnatal CMV infection is frequently asymptomatic and rarely causes disease in immunocompetent individuals; however, population-based studies have indi- cated an association between CMV infection and all-cause mortality [2]. Congenital CMV infection (cCMV) is a major cause of childhood deafness and other neurodevelopmental disabilities [3]. Immunological changes during early life likely play an important role in the Viruses 2021, 13, 1987. https://doi.org/10.3390/v13101987 https://www.mdpi.com/journal/viruses