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J Exp Med
. 2026 May 4;223(5):e20251793.
doi: 10.1084/jem.20251793. Epub 2026 Apr 6.
Nasal CD4+ tissue-resident memory T cells provide cross-protective immunity to influenza
Nimitha R Mathew 1 , Romain Gailleton 1 , Lydia Scharf 1 , Karin Schön 1 , Josue Enriquez 1 , Hannes Axelsson 1 , Anneli Strömberg 1 , Nils Lycke 1 , Mats Bemark 1 2 3 , Ka-Wei Tang 4 5 , Davide Angeletti 1 6
Affiliations
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.
. 2026 May 4;223(5):e20251793.
doi: 10.1084/jem.20251793. Epub 2026 Apr 6.
Nasal CD4+ tissue-resident memory T cells provide cross-protective immunity to influenza
Nimitha R Mathew 1 , Romain Gailleton 1 , Lydia Scharf 1 , Karin Schön 1 , Josue Enriquez 1 , Hannes Axelsson 1 , Anneli Strömberg 1 , Nils Lycke 1 , Mats Bemark 1 2 3 , Ka-Wei Tang 4 5 , Davide Angeletti 1 6
Affiliations
- PMID: 41941276
- PMCID: PMC13052815
- DOI: 10.1084/jem.20251793
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.