CXCR3+ effector regulatory T cells associate with disease tolerance during lower respiratory pneumovirus infection

• Published in: Immunology 2024-07, Vol.172 (3), p.500-515
• Main Authors: Sebina, Ismail, Ngo, Sylvia, Rashid, Ridwan B., Alorro, Mariah, Namubiru, Patricia, Howard, Daniel, Ahmed, Tufael, Phipps, Simon
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Attenuation; Chemokine CXCL10 - metabolism; Chemokine receptors; CXCL10 protein; CXCR3 protein; Dendritic cells; Diet; Dietary fiber; Dietary intake; Disease Models, Animal; Disease tolerance; Effector cells; Female; Flow cytometry; Food intake; Immune Tolerance; Immunological tolerance; Immunoregulation; Infants; Infections; Juveniles; Lung - immunology; Lung - virology; Lungs; Lymph nodes; Lymph Nodes - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Microbiomes; Mucosal immunology; Neonates; Nutrient deficiency; Pathogenesis; Phenotypes; Pneumovirus Infections - immunology; Receptors, CXCR3 - metabolism; regulatory T cells; Respiratory tract infection; T-Lymphocytes, Regulatory - immunology; viral infections
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13790

Lifestyle factors like poor maternal diet or antibiotic exposure disrupt early life microbiome assembly in infants, increasing the risk of severe lower respiratory infections (sLRI). Our prior studies in mice indicated that a maternal low‐fibre diet (LFD) exacerbates LRI severity in infants by impairing recruitment of plasmacytoid dendritic cells (pDC) and consequently attenuating expansion of lung regulatory T (Treg) cells during pneumonia virus of mice (PVM) infection. Here, we investigated whether maternal dietary fibre intake influences Treg cell phenotypes in the mediastinal lymph nodes (mLN) and lungs of PVM‐infected neonatal mice. Using high dimensional flow cytometry, we identified distinct clusters of regulatory T cells (Treg cells), which differed between lungs and mLN during infection, with notably greater effector Treg cell accumulation in the lungs. Compared to high‐fibre diet (HFD)‐reared pups, frequencies of various effector Treg cell subsets were decreased in the lungs of LFD‐reared pups. Particularly, recruitment of chemokine receptor 3 (CXCR3+) expressing Treg cells was attenuated in LFD‐reared pups, correlating with lower lung expression of CXCL9 and CXCL10 chemokines. The recruitment of this subset in response to PVM infection was similarly impaired in pDC depleted mice or following anti‐CXCR3 treatment, increasing immunopathology in the lungs. In summary, PVM infection leads to the sequential recruitment and expansion of distinct Treg cell subsets to the lungs and mLN. The attenuated recruitment of the CXCR3+ subset in LFD‐reared pups increases LRI severity, suggesting that strategies to enhance pDCs or CXCL9/CXCL10 expression will lower immune‐mediated pathogenesis. High dimensional flow cytometry reveals unique subsets of regulatory T cells essential for preventing severe lung damage in neonatal mice experiencing acute lower respiratory infection.