The origin of regulatory from the effector cells in LAG-3-marked Th1 immunity against severe influenza virus infection

Avijit Dutta, Chen Yiu Hung, Tse Ching Chen, Chia Shiang Chang, Sung Han Hsiao, Yung Chang Lin, Chun Yen Lin, Ching Tai Huang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

2 Scopus citations


In severe respiratory virus infections, including influenza, an exaggerated host immune response has been linked to the severe disease and death. Control of the overwhelming immune response is thus essential. Efforts with broad-spectrum immunosuppressive agents such as steroids are disappointing. A better understanding of host immune response using animal experimental system is required to avoid undesired outcome of experimental manipulation. Following severe influenza virus infection in influenza hemagglutinin antigen-specific transgenic mouse experimental model, step-wise evolving cells from a pool of naïve hemagglutinin-specific CD4+ T cells were studied for phenotypic, genomic, and functional characterization in vivo. Naïve CD4+ T cells respond with Th1 commitment in the absolute majority. They first develop into LAG-3MedIFN-γ-secreting Th1 effectors and then evolve into LAG-3HighIFN-γ-not-secreting regulators with increasing LAG-3 expression upon continuous activation and cell division. The LAG-3MedIFN-γ-secreting effectors contribute to inflammation, boost inflammatory response of cognate antigen-specific CD8+ T cells, and aggravate the disease despite facilitated virus clearance. In contrast, LAG-3High regulators do not contribute to inflammation, suppress CD8+ T cell inflammatory response, alleviate lung pathology, and ameliorate the disease with preserved virus clearance. Moderated CD8+ T cells retain proliferative capacity, and persist beyond virus clearance. Such moderation is distinct from Foxp-3+ regulator-mediated suppression, which suppresses proliferative and inflammatory responses of the CD8+ T cells and impairs virus clearance with inflammation alleviation. Origin of regulatory from the effector cells of LAG-3-marked Th1 immunity alleviates lung inflammation without impairment of virus eradication.

Original languageEnglish
Pages (from-to)167-184
Number of pages18
Issue number2
StatePublished - 06 2023

Bibliographical note

© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.


  • Foxp-3
  • Foxp-3LAG-3 Treg cells
  • LAG-3
  • T-bet
  • Th1 immunity
  • hemagglutinin-specific CD4 T cells
  • inflammation
  • severe influenza
  • Hemagglutinins/metabolism
  • Humans
  • Inflammation/metabolism
  • Mice, Transgenic
  • Orthomyxoviridae
  • Communicable Diseases
  • CD8-Positive T-Lymphocytes
  • Animals
  • Th1 Cells
  • Influenza, Human
  • Mice
  • Orthomyxoviridae Infections


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