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High activity of peripheral blood γδ T cells in term and preterm neonates

Presented at the Neonatal Society 2007 Summer Meeting (programme).

Haque SFY1, Gibbons DL2, Hamilton K2, Carr R1, Hayday AC1

1 Department of Immunobiology, Guy's and St. Thomas' Hospital, King's College London, London SE1 9RT, UK
2 Department Haematology, Guy's and St. Thomas' Hospital, King's College London, London SE1 9RT, UK

Background: Newborn T cell immunity is very different from adults (1), but remains poorly understood. This is important because the newborn faces precipitous encounter with environmental challenges. It is known from animal studies that a population of T lymphocytes, γδ T cells, appear functionally more active at birth than the more abundant αβ cells and provide important immunoprotection in the newborn period (2). The aim of the studies reported here were to further our understanding of T cell function in human neonates.

Methods: Whole blood assay: Peripheral blood T cells obtained from 8 adults, 5 term newborn cord bloods and peripheral blood from 9 preterm infants (26-32 weeks gestation) at birth and again aged 1 month, were analysed ex vivo for intracellular cytokine production following overnight stimulation. T cell cloning: Mononuclear cells were isolated from blood samples and sorted into pure αβ and γδ T cell subpopulations. The 2 populations were then maintained in long-term culture. In this way αβ and γδ T cell clones were established from 2 adults, a single healthy term delivery cord blood and from preterm twins. The samples were obtained with informed consent. The study was approved by the St. Thomas’ Research Ethics Committee.

Results: Comparative analysis of the fresh ex vivo and cloned T cell sub-populations led to 4 novel observations. First, a lower percentage of αβ and γδ cells are capable of TNFα production in neonates relative to adults. Some recovery of this deficiency is evident in preterm babies by 1 month after birth, at a time that would ordinarily be pre-partum. Therefore, TNFα competence appears environmentally rather then developmentally programmed. Second, neonatal αβ T cells are profoundly deficient in IFNγ production and there is no increase in this capacity 1 month after birth. By contrast, neonatal γδ T cells actively produce IFNγ upon stimulation, and this response is higher in preterm than in term neonates. Similar to the ex vivo data, the majority of neonatal αβ clones are profoundly deficient in IFNγ production, whereas this is not true for neonatal γδ clones, which also readily produce “adult quantities” of GM-CSF and TRAIL (TNF-related apoptosis inducing ligand). Third, the derived T cell clones permitted more detailed examination of γδ subtypes. We note that neonatal γδ clones make IL-4 and IL-5 (Th2 cytokines) and the immunosuppressive cytokine IL-10, which is not produced at all by adult Vγ9+ clones. These pleiotropic activities of human neonatal γδ clones appear to be determined by the type of T cell receptor expressed. Vδ1+ γδ cells, believed to provide the first line of defence in the gut mucosa, have broad functional potential whereas Vγ9+ gd cells, thought to play a role in the defence against intracellular pathogens, polarise to either a Th1- or Th2-like profile. Finally, we demonstrate that the pattern recognition toll-like receptor, TLR3 is expressed more highly on γδ cells than αβ cells. Moreover, TLR3 protein and mRNA expression is higher in γδ cells from cord blood compared with adults and preterm samples.

Conclusion: The successful and novel generation of T cell clones from human neonates allowed a more detailed examination of function than is possible from small volume fresh blood samples. We propose that high TLR3 expression together with high IFNγ production indicate an important role for γδ cells in human neonates, providing protection before the full maturation of the αβ compartment. The breadth of neonatal γδ cell activity may reflect their potential to promote appropriate responses to the wide range of immunological challenges faced by the newborn.

1. Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol. 2004;4:553-564.
2. Ramsburg E, Tigelaar R, Craft J, Hayday A. Age-dependent requirement for gd T cells in the primary but not secondary protective immune response against an intestinal parasite. J Exp Med. 2003;198:1403- 1414.

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