Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants

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Abstract

In spite of their precipitous encounter with the environment, newborn infants cannot readily mount T helper type 1 (TH1) cell antibacterial and antiviral responses. Instead, they show skewing toward TH2 responses, which, together with immunoregulatory functions, are thought to limit the potential for inflammatory damage, while simultaneously permitting intestinal colonization by commensals1,2,3. However, these collective capabilities account for relatively few T cells. Here we demonstrate that a major T cell effector function in human newborns is interleukin-8 (CXCL8) production, which has the potential to activate antimicrobial neutrophils and γδ T cells. CXCL8 production was provoked by antigen receptor engagement of T cells that are distinct from those few cells producing TH1, TH2 and TH17 cytokines, was co-stimulated by Toll-like receptor signaling, and was readily apparent in preterm babies, particularly those experiencing neonatal infections and severe pathology. By contrast, CXCL8-producing T cells were rare in adults, and no equivalent function was evident in neonatal mice. CXCL8 production counters the widely held view that T lymphocytes in very early life are intrinsically anti-inflammatory, with implications for immune monitoring, immune interventions (including vaccination) and immunopathologies. It also emphasizes qualitative distinctions between infants' and adults' immune systems.

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Figure 1: CXCL8-producing T cells in infants.
Figure 2: The surface phenotype of CXCL8-producing T cells.
Figure 3: Flagellin co-stimulates CXCL8 production from neonatal T cells.
Figure 4: Infants with illness display CXCL8-producing T cells.

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Acknowledgements

We thank P. Hunter for helpful discussions, T. Hayday for flow cytometry, K. Rouault-Pierre (London Research Institute, Cancer Research UK) for cord blood, Pierre Vantourout (London Research Institute, Cancer Research UK) for γδ T cell lines, M. Greaves for advice on T-ALL, P. Chakravarty for microarray analysis and M. Leite-de-Moraes for support of mouse studies. P.F. was funded by a strategic research grant from the Barts and the London Charity, A.V. and N.J.S. by the UK National Institute for Health Research (NIHR) Great Ormond Street Hospital (GOSH) Biomedical Research Centre (BRC), N.J.S. partly by GOSH Children's charity, and D.G., R.C. and A.H. by the Guy's and St. Thomas', charity, the NIHR Biomedical Research Centre at Guy's and St. Thomas', Hospital and King's College, and by a Wellcome Trust Programme Grant to A.H.

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D.G. co-designed the study, undertook all experiments with human materials, evaluated the results and co-wrote the manuscript; P.F. co-designed the study, was attending physician to the clinical trial to which the study is annexed, provided human samples, evaluated clinical data and edited the manuscript; A.V. undertook the immunohistology; M.-L.M. undertook the animal model experiments; N.J.S. evaluated immunohistology and provided samples; K.C. designed and supervised the clinical trial to which the study is annexed and edited the manuscript; R.C. co-formulated the study as an annex to a clinical trial and edited the manuscript; N.K. co-supervised the analysis of pathology and edited the manuscript; A.H. co-designed the study, evaluated the results and co-wrote the manuscript.

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Correspondence to Deena Gibbons or Adrian Hayday.

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The authors declare no competing financial interests.

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Gibbons, D., Fleming, P., Virasami, A. et al. Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants. Nat Med 20, 1206–1210 (2014). https://doi.org/10.1038/nm.3670

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