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

Author:

Sebina Ismail123ORCID,Ngo Sylvia1,Rashid Ridwan B.12,Alorro Mariah1,Namubiru Patricia12,Howard Daniel12,Ahmed Tufael13,Phipps Simon1234

Affiliation:

1. Respiratory Immunology Laboratory QIMR Berghofer Medical Research Institute Herston Queensland Australia

2. School of Biomedical Sciences, Faculty of Medicine The University of Queensland Brisbane Queensland Australia

3. School of Biomedical Sciences Queensland University of Technology Brisbane Queensland Australia

4. Australian Infectious Diseases Research Centre The University of Queensland Brisbane Queensland Australia

Abstract

AbstractLifestyle 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.

Funder

National Health and Medical Research Council

Publisher

Wiley

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