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

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 commensals. 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.

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

“…Large clinical studies testing associations between functional MIF polymorphisms and MIF expression levels with susceptibility to or severity of neonatal sepsis are now required to substantiate whether MIF represents a potential attractive target for immune-modulating adjunctive therapies for neonatal sepsis. Adding to the recent studies challenging the idea that the neonatal immune system is purely immature (71)(72)(73)(74)(75), the recognition of a unique role for MIF in regulating innate immunity supports the concept that neonatal immune responses are tightly regulated by a balance of pro-and antiinflammatory mediators.…”

Neonatal thymectomy reveals differentiation and plasticity within human naive T cells

“…Naive CD4 + T cells indeed lack substantial production of effector cytokines that define the different T helper subset signatures. However, it was recently shown that human naive CD4 + T cells have the unique capability of producing large amounts of IL-8 (CXCL8), indicating that these cells do have a specific effector function, at least in newborns (2). How this functional signature relates to naive T cell dynamics and aging is unknown.…”

An Immunological Perspective on Neonatal Sepsis

“…For example, neonatal immune cells can produce developmentally unique cytokine isoforms, and two examples have been reported in humans with IL-4 and CXCL8 (also known as interleukin-8 (IL-8) [32,33]. In addition, a large proportion of human naïve neonatal T cells are able to produce the CXCL8 chemokine upon stimulation [34]. The production of CXCL8 by neonatal T cells is unique in that it occurs in absence of effector differentiation, specifically in CD31 T cells that have recently emerged from the thymus [35].…”

“…CXCL8 is a powerful neutrophil chemoattractant and is a chemokine that has no direct counterpart in mice [36]. Given the important role of neutrophils in neonatal sepsis, production of this chemokine may play a crucial role during an early response to infection as suggested by data showing an accumulation of CXCL8-producing CD4+ T cells during sepsis or necrotizing enterocolitis (NEC) [34]. In mice, innate γδ T cells have been shown to activate neutrophils directly during infections through a production of large amounts of IL-17, an important cytokine which facilitates the development of mucosal immunity [37].…”

“…In mice, innate γδ T cells have been shown to activate neutrophils directly during infections through a production of large amounts of IL-17, an important cytokine which facilitates the development of mucosal immunity [37]. However, human neutrophils generally respond poorly to IL-17 [34]. Presumably, CXCL8-producing naïve T cells could provide immediate help by sanctioning the activation of neutrophils in humans, in a PRR-dependent manner during an infection.…”