title: NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection.
abstract: CD4 T cells can differentiate into multiple effector subsets, including ThCTL that mediate MHC class II-restricted cytotoxicity. Although CD4 T cell-mediated cytotoxicity has been reported in multiple viral infections, their characteristics and the factors regulating their generation are unclear, in part due to a lack of a signature marker. We show in this article that, in mice, NKG2C/E identifies the ThCTL that develop in the lung during influenza A virus infection. ThCTL express the NKG2X/CD94 complex, in particular the NKG2C/E isoforms. NKG2C/E+ThCTL are part of the lung CD4 effector population, and they mediate influenza A virus-specific cytotoxic activity. The phenotype of NKG2C/E+ThCTL indicates they are highly activated effectors expressing high levels of binding to P-selectin, T-bet, and Blimp-1, and that more of them secrete IFN-γ and readily degranulate than non-ThCTL. ThCTL also express more cytotoxicity-associated genes including perforin and granzymes, and fewer genes associated with recirculation and memory. They are found only at the site of infection and not in other peripheral sites. These data suggest ThCTL are marked by the expression of NKG2C/E and represent a unique CD4 effector population specialized for cytotoxicity.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Nikki B
authors.initials: NB
authors.lastname: Marshall
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Allen M
authors.initials: AM
authors.lastname: Vong
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Priyadharshini
authors.identifier: 0000-0003-2058-6339
authors.initials: P
authors.lastname: Devarajan
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Brauner
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Yi
authors.identifier: 0000-0002-3266-1781
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Ribhu
authors.initials: R
authors.lastname: Nayar
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schutten
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Castonguay
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Leslie J
authors.identifier: 0000-0001-6031-7542
authors.initials: LJ
authors.lastname: Berg
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; and.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Stephen L
authors.identifier: 0000-0002-0020-6637
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605; susan.swain@umassmed.edu.
authors.forename: Susan L
authors.identifier: 0000-0002-3643-8018
authors.initials: SL
authors.lastname: Swain
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000145:classification / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D009980:Influenza A virus; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000032:analysis*; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D014157:Transcription Factors / Q000032:analysis
chemical_list: D015415:Biomarkers; C527060:Klrc2 protein, mouse; D055654:NK Cell Lectin-Like Receptor Subfamily C; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1