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Gamma-delta T-lymphocyte function in newborn infants

Presented at the Neonatal Society 2005 Summer Meeting (programme).

Hamilton K1, Gibbons DL2, Elliott M3, Hayday AC2, Carr R1

1 Department of Haematology, Guy's and St. Thomas' Hospital, King's College London, UK
2 Department of Immunobiology, Guy's and St. Thomas' Hospital, King's College London, UK
3 Department of Neonatal Paediatrics, Guy's and St. Thomas' Hospital, King's College London, UK

Background: Innate immunity in the newborn is immature, as demonstrated by the inability of neonates to resolve bacteraemia caused by organisms of even low pathogenicity. However, most newborns do not develop bacteraemia during normal colonisation of the gut, which suggests that the newborn gut wall is an effective immunological barrier. Recent evidence from mice suggests that, in the newborn, gamma delta T-lymphocytes (γδ cells), which comprise a major component (up to 30%) of gut wall intra-epithelial lymphocytes (IELs), are functionally more mature than alpha beta T-lymphocytes (αβ cells) (1). Alpha-beta cells are the predominant (>95%) T-lymphocyte population in peripheral blood (PB) and lymph nodes, and provide the major component of systemic cell mediated immunity. The functional maturity and role of γδ T-cells in human neonates is unknown. The purpose of this study was to compare the functional maturity of PB αβ and γδ T-cells from preterm neonates, term neonates and adults.

Methods: Blood was drawn from 10 preterm neonates (GA 26-31 weeks) within 72 hours of birth and again at 4 weeks postnatal age. Cord blood was also obtained from 5 normal term infants, and 8 healthy adults. Whole blood was incubated with PMA and ionomycin to stimulate cytokine production, together with the Golgi channel blockers monensin and brefeldin A to inhibit cytokine secretion. Cells were harvested after 16 hours, stained for CD3 and TCR-γδ to identify lymphocyte subsets, permeabilised and stained for accumulated intracellular IFNγ, IL-2 and TNFα. The proportion of cells synthesising each cytokine was counted on a MoFlo 6 colour flow cytometer. The study was approved by the Guy’s Hospital Research Ethics Committee.

Results: Preterm and term neonates show an almost complete absence of IFNγ producing αβ T-cells (p<0.001, neonate groups v adults), with no functional maturation by 1 month postnatal age. In contrast, the proportion of preterm neonate γδ cells producing IFNγ was 20 times that of their αβ cells (p=0.001). Neonate γδ cells also actively secrete IL-2 (NS, neonate groups v adults), whereas significantly fewer newborn αβ cells secrete IL-2 than in adults (p<0.001). The same maturity was not seen for TNFα, which had equally poor production by newborn γδ and αβ cells.

Discussion: These data demonstrate that, in newborn human infants, peripheral blood γδ T-cells have more mature production of the protective TH1 cytokines IFNγδ and IL-2 than αβ T-cells. In newborn mice γδ IELs provide protection against intestinal infection before maturation of αβ Tcell function1. We therefore hypothesise that in the newborn human infant γδ intra-epithelial lymphocytes may similarly provide the mechanism which prevents bacterial translocation across the gut wall during normal gut colonisation.

1. Ramsburg E, Tigelaar R, Craft J, Hayday A. J Exp Med 2003; 198: 1403-1414

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