Neonates harbour highly active γδ T cells with selective impairments in preterm infants

Abstract

Acknowledgement of the breadth of T-cell pleiotropy has provoked increasing interest in the degree to which functional responsiveness is elicited by environmental cues versus differentiation. This is particularly relevant for young animals requiring rapid responses to acute environmental exposure. In young mice, cd T cells are disproportionately important for immuno-protection. To examine the situation in humans, we compared populations and clones of T cells from term and preterm babies, and adults. By comparison with ab T cells, neonate-derived cd cells show stronger, pleiotropic functional responsiveness, and lack signatory deficits in IFN-c production. Emphasising the acquisition of functional competence in utero, IFN-c was produced by cd cells sampled from premature births, and, although one month's post-partum environmental exposure invariably increased their TNF-a production, it had no consistent effect on IFN-c or IL-2. In sum, cd cells seem well positioned at birth to contribute to immuno-protection and immuno-regulation, possibly compensating for selective immaturity in the ab compartment. With regard to the susceptibilities of preterm babies to viral infection, cd cells from preterm neonates were commonly impaired in Toll-like receptor-3 and -7 expression and compared with cells from term babies failed to optimise cytokine production in response to coincident TCR and TLR agonists. Key words: Neonate immunity . gd T cells . Toll-like receptors Supporting Information available online IntroductionAfter the protected intra-uterine environment, birth exposes the newborn mammal to precipitous encounter with antigens. Although several groups have concluded that lymphocytes from young animals can, under optimal conditions, successfully mount robust immune responses [1][2][3], it is also clear de facto that immune responses in children and young animals are sub-optimal and that neonates and infants are more vulnerable to infections, and respond less well to most vaccines than do older children or adults [4][5][6]. While different studies primarily attribute the problem to intrinsic defects in à These authors contributed equally to this work. 1794T cells or APC, respectively, it is likely that both are impaired in vivo [7].One particularly striking deficit reported in neonatal ab T cells is in IFN-g production, which underpins Th1 responses to intracellular parasites, bacteria and certain viruses. Such defects in conventional T-cell responses have fuelled the hypothesis that gd T cells, that are relatively rare in the blood and lymphoid circulation of adults, may contribute disproportionately to immune function in the young. Supporting this, weanling gd cell-deficient (TCR-d À/À ) mice, relative to wild-type counterparts, show a delayed acquisition of immune resistance to the natural gut pathogen, Eimeria vermiformis ([8] and our unpublished data). There is a similar susceptibility of young TCR-d À/À mice to infection by Cryptosporidium [9]. Provocatively, very early T-cell development is disproportionately di...

Murine CD27 (−) Vγ6 (+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

“…In comparison with their murine counterparts, human circulating γδ T lymphocytes are extremely polarized toward IFN-γ production from early stages of life (8,65). By contrast, IL-17 (+) γδ T cells are very rare in the peripheral blood of healthy individuals (65,66), but accumulate significantly in pathological conditions such as bacterial meningitis (67) or psoriasis (68).…”

“…Human γδ T cells also possess IFN-γ-secreting potential, which is displayed immediately at birth (8) and display cytotoxicity against tumor lines of diverse origin, including epithelial (9,10) and hematological (11,12) tumors. This has prompted the development of cancer clinical trials targeting γδ T cells, which have produced encouraging, albeit highly variable, degrees of therapeutic responses (13)(14)(15).…”

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

“…Indeed, one of the last cytokines to reach adult levels after birth is the Th1-promoting cytokine IL-12 (IL-12p70) (27). Originally proposed as a hypothesis by Adrian Hayday (1), there is increasing evidence, including our own results, that γδ T cells are important in early life (28)(29)(30)(31)(32)(33). Although in humans circulating T cells can be detected as early as 12.5 wk gestation, most information on T cells in early life, including γδ T cells, is derived from studies on cord blood at term delivery (>37 wk gestation) (34).…”

Mechanisms underlying lineage commitment and plasticity of human γδ T cells

“…23 In human Vc9Vd2 T cells, polarization towards IL-17 production is efficiently induced by coordinated antigen stimulation of the specific TCR, a combination of the polarizing cytokines IL-1b, IL-6, transforming growth factor (TGF)-b and IL-23 and aryl hydrocarbon receptor (AHR) ligands. 8 Differentiation to cd17 T cells is due to high levels of RORC and AHR expression versus a low level of T-bet expression in these cells.…”