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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Zaghouani, H., Hoeman, C.M. & Adkins, B. Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol. 30, 585–591 (2009).
Hebel, K. CD4+ T cells from human neonates and infants are poised spontaneously to run a non-classical IL-4 program. J. Immunol. 192, 5160–5170 (2014).
Gibbons, D.L. et al. Neonates harbour highly active γδ T cells with selective impairments in preterm infants. Eur. J. Immunol. 39, 1794–1806 (2009).
Carr, R., Brocklehurst, P., Dore, C.J. & Modi, N. Granulocyte-macrophage colony stimulating factor administered as prophylaxis for reduction of sepsis in extremely preterm, small for gestational age neonates (the PROGRAMS trial): a single-blind, multicentre, randomised controlled trial. Lancet 373, 226–233 (2009).
Berrington, J.E., Hearn, R.I., Bythell, M., Wright, C. & Embleton, N.D. Deaths in preterm infants: changing pathology over 2 decades. J. Pediatr. 160, 49–53.e1 (2012).
Costeloe, K.L. et al. Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies). Br. Med. J. 345, e7976 (2012).
Junge, S. et al. Correlation between recent thymic emigrants and CD31+ (PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children. Eur. J. Immunol. 37, 3270–3280 (2007).
Kimmig, S. et al. Two subsets of naïve T-helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J. Exp. Med. 195, 789–794 (2002).
Mold, J.E. et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322, 1562–1565 (2008).
Sharma, N., Akhade, A.S. & Qadri, A. Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells. J. Leukoc. Biol. 93, 521–528 (2013).
Luster, A.D. Chemokines—chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 338, 436–445 (1998).
Zlotnik, A. & Yoshie, O. The chemokine superfamily revisited. Immunity 36, 705–716 (2012).
De Rosa, S.C. et al. Ontogeny of γδ T cells in humans. J. Immunol. 172, 1637–1645 (2004).
Khalaf, H., Jass, J. & Olsson, P.E. The role of calcium, NF-κB and NFAT in the regulation of CXCL8 and IL-6 expression in Jurkat T-cells. Int. J. Biochem. Mol. Biol. 4, 150–156 (2013).
Nanthakumar, N.N., Fusunyan, R.D., Sanderson, I. & Walker, W.A. Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc. Natl. Acad. Sci. USA 97, 6043–6048 (2000).
Levy, E. et al. Distinct roles of TLR4 and CD14 in LPS-induced inflammatory responses of neonates. Pediatr. Res. 66, 179–184 (2009).
Thornton, N.L., Cody, M.J. & Yost, C.C. Toll-like receptor 1/2 stimulation induces elevated interleukin-8 secretion in polymorphonuclear leukocytes isolated from preterm and term newborn infants. Neonatology 101, 140–146 (2012).
Taur, Y. et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoetic stem cell transplantation. Clin. Infect. Dis. 55, 905–914 (2012).
Chiaretti, S. et al. Gene expression profile of adult T-cell acute lymphocytic leukemia identifies distinct subsets of patients with different response to therapy and survival. Blood 103, 2771–2778 (2004).
Heeger, P.S. et al. Decay-accelerating factor modulates induction of T cell immunity. J. Exp. Med. 201, 1523–1530 (2005).
Pelletier, M. et al. Evidence for a cross-talk between human neutrophils and Th17 cells. Blood 115, 335–343 (2010).
Taylor, P.R. et al. Activation of neutrophils by autocrine IL17A–IL17RC interactions during fungal infection is regulated by IL-6, IL-23, RORγT and dectin-2. Nat. Immunol. 15, 143–151 (2014).
Schröder, J.M., Mrowietz, U. & Christophers, E. Purification and partial biologic characterization of a human lymphocyte-derived peptide with potent neutrophil-stimulating activity. J. Immunol. 140, 3534–3540 (1988).
Kyriakakis, E. et al. Invariant natural killer T cells: linking inflammation and neovascularization in human atherosclerosis. Eur. J. Immunol. 40, 3268–3279 (2010).
Dagna, L. et al. Skewing of cytotoxic activity and chemokine production, but not of chemokine receptor expression, in human type-1/-2 γδ T lymphocytes. Eur. J. Immunol. 32, 2934–2943 (2002).
Laggner, U. et al. Identification of a novel proinflammatory human skin-homing Vg9Vd2 T cell subset with a potential role in psoriasis. J. Immunol. 187, 2783–2793 (2011).
Himmel, M.E. et al. Human CD4+ FOXP3+ regulatory T cells produce CXCL8 and recruit neutrophils. Eur. J. Immunol. 41, 306–312 (2011).
Schaerli, P. et al. Characterization of human T cells that regulate neutrophilic skin inflammation. J. Immunol. 173, 2151–2158 (2004).
Chorro, L. & Geissmann, F. Development and homeostasis of 'resident' myeloid cells: the case of the Langerhans cell. Trends Immunol. 31, 438–445 (2010).
Havran, W.L. & Allison, J.P. Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335, 443–445 (1988).
Mold, J.E. et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330, 1695–1699 (2010).
Carr, R. The role of colony stimulating factors and immunoglobulin in the prevention and treatment of neonatal infection. Arch. Dis. Child. Fetal Neonatal Ed. 98, F192–F194 (2013).
Panero, A. et al. Interleukin 6 in neonates with early and late onset infection. Pediatr. Infect. Dis. J. 16, 370–375 (1997).
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.
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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