NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection [IMMUNE REGULATION]

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.

Footnotes

  • This work was supported by National Institutes of Health Grants P01AI046539 and R01AI118820 (to S.L.S.), U19AI109858 (to Dr. Raymond M. Welsh), and T32-AI 007349 (to A.M.V.).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    A/PR8
    A/Puerto Rico/8/34
    A/PR8-OVAII
    A/Puerto Rico/8/34-OVA323–339
    B6
    C57BL/6
    BAL
    bronchioalveolar lavage
    CKO
    conditional knock out
    dLN
    draining mediastinal lymph node
    dpi
    day postinfection
    GrB
    granzyme B
    HA
    hemagglutinin
    IAV
    influenza A virus
    i.n.
    intranasally
    KO
    knockout
    LCMV
    lymphocytic choriomeningitis virus
    MHC-II
    MHC class II
    NP
    nucleoprotein
    SLO
    secondary lymphoid organ
    TFH
    T follicular helper
    Tg
    transgenic
    UMMS
    University of Massachusetts Medical School
    WT
    wild type.
  • Received July 26, 2016.
  • Accepted December 5, 2016.

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