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Nasal CD4+ tissue-resident memory T cells provide cross-protective immunity to influenza

Mathew, Nimitha R ; Gailleton, Romain ; Scharf, Lydia ; Schön, Karin ; Enriquez, Josue ; Axelsson, Hannes ; Strömberg, Anneli ; Lycke, Nils ; Bemark, Mats LU orcid and Tang, Ka-Wei , et al. (2026) In The Journal of experimental medicine 223(5). p.1-26
Abstract

CD4 tissue-resident memory T cells (TRM) are crucial adaptive immune components involved in preventing influenza A virus (IAV) infection. Despite their importance, their physiological role in the upper respiratory tract, the first site of contact with IAV, remains unclear. Here, we find that, after IAV infection, antigen-specific CD4 TRM persist in the nasal tissue (NT) compartment after infection and provide protection upon heterosubtypic challenge. Single-cell RNA-sequencing analysis reveals that NT CD4 TRM are heterogeneous and transcriptionally distinct as compared with their lung counterparts. Mechanistically, we demonstrate that the CXCR6-CXCL16 axis promotes CD4 TRM residency in the NT. Furthermore, we show that the NT of mice... (More)

CD4 tissue-resident memory T cells (TRM) are crucial adaptive immune components involved in preventing influenza A virus (IAV) infection. Despite their importance, their physiological role in the upper respiratory tract, the first site of contact with IAV, remains unclear. Here, we find that, after IAV infection, antigen-specific CD4 TRM persist in the nasal tissue (NT) compartment after infection and provide protection upon heterosubtypic challenge. Single-cell RNA-sequencing analysis reveals that NT CD4 TRM are heterogeneous and transcriptionally distinct as compared with their lung counterparts. Mechanistically, we demonstrate that the CXCR6-CXCL16 axis promotes CD4 TRM residency in the NT. Furthermore, we show that the NT of mice and humans contains a high frequency of Th17 CD4 TRM that aid in local viral clearance and in reducing tissue damage. Collectively, our results support a robust physiological role for NT CD4 TRM in local protection during heterosubtypic IAV infection.

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publication status
published
subject
keywords
Animals, Humans, Memory T Cells/immunology, Immunologic Memory/immunology, Mice, CD4-Positive T-Lymphocytes/immunology, Orthomyxoviridae Infections/immunology, Influenza A virus/immunology, Mice, Inbred C57BL, Receptors, CXCR6/metabolism, Influenza, Human/immunology, Th17 Cells/immunology, Lung/immunology, Female
in
The Journal of experimental medicine
volume
223
issue
5
article number
e20251793
pages
1 - 26
publisher
Rockefeller University Press
external identifiers
  • pmid:41941276
  • scopus:105035036207
ISSN
1540-9538
DOI
10.1084/jem.20251793
language
English
LU publication?
yes
additional info
© 2026 Mathew et al.
id
1b26cb1a-909d-4812-b265-977d5900fce3
date added to LUP
2026-04-08 09:57:33
date last changed
2026-06-10 09:27:01
@article{1b26cb1a-909d-4812-b265-977d5900fce3,
  abstract     = {{<p>CD4 tissue-resident memory T cells (TRM) are crucial adaptive immune components involved in preventing influenza A virus (IAV) infection. Despite their importance, their physiological role in the upper respiratory tract, the first site of contact with IAV, remains unclear. Here, we find that, after IAV infection, antigen-specific CD4 TRM persist in the nasal tissue (NT) compartment after infection and provide protection upon heterosubtypic challenge. Single-cell RNA-sequencing analysis reveals that NT CD4 TRM are heterogeneous and transcriptionally distinct as compared with their lung counterparts. Mechanistically, we demonstrate that the CXCR6-CXCL16 axis promotes CD4 TRM residency in the NT. Furthermore, we show that the NT of mice and humans contains a high frequency of Th17 CD4 TRM that aid in local viral clearance and in reducing tissue damage. Collectively, our results support a robust physiological role for NT CD4 TRM in local protection during heterosubtypic IAV infection.</p>}},
  author       = {{Mathew, Nimitha R and Gailleton, Romain and Scharf, Lydia and Schön, Karin and Enriquez, Josue and Axelsson, Hannes and Strömberg, Anneli and Lycke, Nils and Bemark, Mats and Tang, Ka-Wei and Angeletti, Davide}},
  issn         = {{1540-9538}},
  keywords     = {{Animals; Humans; Memory T Cells/immunology; Immunologic Memory/immunology; Mice; CD4-Positive T-Lymphocytes/immunology; Orthomyxoviridae Infections/immunology; Influenza A virus/immunology; Mice, Inbred C57BL; Receptors, CXCR6/metabolism; Influenza, Human/immunology; Th17 Cells/immunology; Lung/immunology; Female}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{5}},
  pages        = {{1--26}},
  publisher    = {{Rockefeller University Press}},
  series       = {{The Journal of experimental medicine}},
  title        = {{Nasal CD4+ tissue-resident memory T cells provide cross-protective immunity to influenza}},
  url          = {{http://dx.doi.org/10.1084/jem.20251793}},
  doi          = {{10.1084/jem.20251793}},
  volume       = {{223}},
  year         = {{2026}},
}