title: Human cytomegalovirus elicits fetal gammadelta T cell responses in utero.
abstract: The fetus and infant are highly susceptible to viral infections. Several viruses, including human cytomegalovirus (CMV), cause more severe disease in early life compared with later life. It is generally accepted that this is a result of the immaturity of the immune system. gammadelta T cells are unconventional T cells that can react rapidly upon activation and show major histocompatibility complex-unrestricted activity. We show that upon CMV infection in utero, fetal gammadelta T cells expand and become differentiated. The expansion was restricted to Vgamma9-negative gammadelta T cells, irrespective of their Vdelta chain expression. Differentiated gammadelta T cells expressed high levels of IFN-gamma, transcription factors T-bet and eomes, natural killer receptors, and cytotoxic mediators. CMV infection induced a striking enrichment of a public Vgamma8Vdelta1-TCR, containing the germline-encoded complementary-determining-region-3 (CDR3) delta1-CALGELGDDKLIF/CDR3gamma8-CATWDTTGWFKIF. Public Vgamma8Vdelta1-TCR-expressing cell clones produced IFN-gamma upon coincubation with CMV-infected target cells in a TCR/CD3-dependent manner and showed antiviral activity. Differentiated gammadelta T cells and public Vgamma8Vdelta1-TCR were detected as early as after 21 wk of gestation. Our results indicate that functional fetal gammadelta T cell responses can be generated during development in utero and suggest that this T cell subset could participate in antiviral defense in early life.
authors.affiliation: Institute for Medical Immunology, Université Libre de Bruxelles, 6041 Gosselies, Belgium. dvermijl@ulb.ac.be
authors.forename: David
authors.initials: D
authors.lastname: Vermijlen
authors.forename: Margreet
authors.initials: M
authors.lastname: Brouwer
authors.forename: Catherine
authors.initials: C
authors.lastname: Donner
authors.forename: Corinne
authors.initials: C
authors.lastname: Liesnard
authors.forename: Marie
authors.initials: M
authors.lastname: Tackoen
authors.forename: Michel
authors.initials: M
authors.lastname: Van Rysselberge
authors.forename: Nicolas
authors.initials: N
authors.lastname: Twité
authors.forename: Michel
authors.initials: M
authors.lastname: Goldman
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marchant
authors.forename: Fabienne
authors.initials: F
authors.lastname: Willems
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000954:Antigens, Surface / Q000378:metabolism; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D002452:Cell Count; D002454:Cell Differentiation / Q000276:immunology; D018925:Chemokines / Q000235:genetics; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D005333:Fetus / Q000276:immunology* / Q000821:virology; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D005865:Gestational Age; D053804:Granzymes / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D011247:Pregnancy; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology*; D019707:Receptors, Chemokine / Q000235:genetics; D055607:Receptors, Natural Killer Cell; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D017252:CD3 Complex; C472562:CD3delta antigen; D018925:Chemokines; D022801:Complementarity Determining Regions; D016207:Cytokines; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019707:Receptors, Chemokine; D055607:Receptors, Natural Killer Cell; D007371:Interferon-gamma; D053804:Granzymes