Host-derived lipids orchestrate pulmonary γδ T cell response to provide early protection against influenza virus infection

Nat Commun. 2021 Mar 26;12(1):1914. doi: 10.1038/s41467-021-22242-9.

Abstract

Innate immunity is important for host defense by eliciting rapid anti-viral responses and bridging adaptive immunity. Here, we show that endogenous lipids released from virus-infected host cells activate lung γδ T cells to produce interleukin 17 A (IL-17A) for early protection against H1N1 influenza infection. During infection, the lung γδ T cell pool is constantly supplemented by thymic output, with recent emigrants infiltrating into the lung parenchyma and airway to acquire tissue-resident feature. Single-cell studies identify IL-17A-producing γδ T (Tγδ17) cells with a phenotype of TCRγδhiCD3hiAQP3hiCXCR6hi in both infected mice and patients with pneumonia. Mechanistically, host cell-released lipids during viral infection are presented by lung infiltrating CD1d+ B-1a cells to activate IL-17A production in γδ T cells via γδTCR-mediated IRF4-dependent transcription. Reduced IL-17A production in γδ T cells is detected in mice either lacking B-1a cells or with ablated CD1d in B cells. Our findings identify a local host-immune crosstalk and define important cellular and molecular mediators for early innate defense against lung viral infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1d / immunology
  • Antigens, CD1d / metabolism
  • Female
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate / immunology
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Influenza A Virus, H1N1 Subtype / physiology
  • Influenza, Human / immunology*
  • Influenza, Human / metabolism
  • Influenza, Human / virology
  • Interferon Regulatory Factors / immunology
  • Interferon Regulatory Factors / metabolism
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Lipids / immunology*
  • Lung / immunology
  • Lung / metabolism
  • Lung / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / virology
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism

Substances

  • Antigens, CD1d
  • Interferon Regulatory Factors
  • Interleukin-17
  • Lipids
  • Receptors, Antigen, T-Cell, gamma-delta
  • interferon regulatory factor-4