Summary auto-generated
This study examined the role of gamma/delta T-lymphocytes (γδ T-cells) in protecting mice against influenza virus infection when treated with trehalose 6,6'-dimycolate (TDM), a mycobacterial glycolipid immunomodulator. Researchers depleted specific immune cell populations and found that removal of γδ T-cells, alpha/beta T-cells (αβ T-cells), or natural killer (NK) cells each significantly impaired the enhanced resistance of TDM-treated mice to lethal influenza infection. To understand the mechanism, the authors generated cell lines expressing influenza hemagglutinin (HA) proteins and tested them as targets for γδ T-cell killing. TDM-activated γδ T-cells demonstrated potent cytotoxic activity against target cells expressing either H1 or H3 HA subtypes in a non-major histocompatibility complex (MHC)-restricted manner. These findings indicate that γδ T-cells contribute to antiviral defense through recognition and destruction of HA-expressing infected cells, working together with αβ T-cells and NK cells to provide comprehensive protection against influenza virus.
Key findings
- Depletion of γδ T-cells, αβ T-cells, or NK cells each significantly reduced the protective effect of TDM treatment against lethal influenza infection, indicating all three cell types are required for optimal defense.
- TDM-activated γδ T-cells exhibited strong cytotoxic activity against target cells expressing influenza hemagglutinin proteins from both H1 and H3 viral strains.
- γδ T-cell killing of HA-expressing targets occurred in an MHC-unrestricted manner, differing from conventional T-cell-mediated cytotoxicity.
- Complementary roles exist between γδ T-cells and αβ T-cells in conferring protection, as depletion of either subset impaired the overall immune response.
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Abstract
Trehalose 6,6'-dimycolate (TDM), an immunomodulator, potentiates non- specific resistance in mice to influenza virus infection. When mice were injected intravenously with TDM, the striking proliferation of a minority of T-lymphocytes bearing gamma/delta T-cell receptors (gamma delta T-cells) that accumulated in granulomatous lungs was thought to be associated with the maintenance of acquired resistance to lethal influenza virus infection. To clarify the cellular basis of the defence against influenza virus, mice were depleted of gamma delta T-cells, alpha/beta (alpha beta) T-cells, or natural killer (NK) cells by in vivo administration of corresponding antibodies prior to influenza virus infection. The depletion of gamma delta T-cells significantly abrogated the augmented resistance of TDM-treated mice to infection, as did depletion of either alpha beta T-cells or NK cells. To gain insight into the functional ability of gamma delta T-cells, we evaluated the cytotoxic activity of this T-cell subset against a panel of target cell lines that were stably transfected with the influenza virus haemagglutinin (HA) gene from A/PR/8/34(H1N1) and A/Aichi/2/68(H3N2) strains. The gamma delta T-cells from TDM-treated mice showed profound cytotoxicity against the target cells expressing HA of either the H1 or H3 subtype, in a non-major histocompatibility complex-restricted manner. Taken together, these results indicate that gamma delta T-cells play a non-specific role, in conjunction with alpha beta T-cells and NK cells, in protecting mice against influenza virus infection, and that the recognition and destruction of HA-expressing target cells by the activated gamma delta T-cells is one of the steps involved in this anti- influenza virus immunosurveillance.