Down-regulation of Th1 responses in human neonates

Cytokines have emerged as critical inducers of Th subset development. In the innate response to intracellular pathogens, Th1 type cytokines, like IL-12 and IFN-γ play a key role in initiating early resistance to the pathogen, and induction of cell-mediated immunity for reviews see 1–4]. IL-12 produced particularly by mononuclear phagocytes and dentritic cells upon direct infection or stimulation with microbial products induces the production of IFN-γ by NK cells and naive T cells. In turn, IFN-γ triggers the IFN-γ receptor (IFN-γR) on monocytes/macrophages to activate the signal transducer and activator of transcription (STAT)-1, a process strongly associated with inreased microbicidal activity of mononuclear phagocytes. IL-12 also selectively promotes the differentiation of naive CD4+ T cells into effector Th1 CD4+ cells, which produce the same effector cytokines, i.e. IFN-γ in addition to IL-2. Therefore, the secretion of IL-12 and a microenvironment dominated by IL-12 and IFN-γ initiates innate resistance to the pathogen and regulates the polarization of T cells to a Th1 response.

Factors that regulate the polarization to either Th1 or Th2 immune response appear to be different in newborns and adults. In general, Th2 responses control extracellular pathogens by initiating antibody secretion by B cells, whereas Th1 responses help to eradicate intracellular microorganisms through activation of macrophages. Human neonates are not able to mount an efficient immune response to a large number of pathogens for reviews see 5–8]. The immaturity of the immune system at birth involves regulatory defects in the production of IgG, but IgG antibodies passively acquired from the mother assure high level of humoral immunity against extracellular bacteria [9,10]. Regulatory defects of cell-mediated immunity against intracellular pathogens, however, are not compensated by maternally derived factors. Accumulating evidence suggests that Th1 responses in newborns are compromised at several steps including deficient production of Th1 type cytokines by neonatal CD4+ T cells and mononuclear phagocytes, and hyporesponsiveness of neonatal macrophages to stimulation by INF-γ 11–20; Table 1]. These deficiencies may be responsible for the apparently weak cellular immunity in newborns biased towards a Th2 type response.

Table 1.

The evolving view of deficient Th1 responses in human neonates

Reported findings	References
Diminished production of IFN-γ by neonatallymphocytes	11, 12
Hypo-responsiveness of neonatal monocytes/macrophagesto IFN-γ	18, 19
Defective STAT-1 phosphorylation in cord monocytesstimulated with IFN-γ	20
Decreased phenotypic expression and function ofcord-derived dendritic cells	16, 17
Diminished production of IL-12 by cord blood mixedmononuclear cells	13, 14
Diminished production of IL-12 by cord-derived dendriticcells	15

Deficiency in IFN-γ production by neonatal T cells in response to mitogen stimulation or bacterial exposure is well-documented [11–13]. IFN-γ deficiency in neonates may be attributed, in addition to lymphocyte immaturity, to decreased production of IL-12 [13,14]. IL-12 is produced mostly by monocytes, macrophages, and dentritic cells. Lee et al.[14] reported diminished production of IL-12 by cord blood mixed mononuclear cells in response to LPS. In a study published in this issue of the Journal, Langrish et al.[15] reported that neonatal dentritic cells derived from cord blood monocytes showed a failure in IL-12 production and had a lower capacity to stimulate IFN-γ production in T cells. This study confirms previous findings [16,17] and provides additional information on Th1 failure in the activity of neonatal dentritic cells.

In contrast to IL-12, IL-2, another potent IFN-γ-inducing cytokine, is produced in nearly equal amounts by both memory and naive T cells from neonatal and adult blood [12]. Therefore the striking discrepancy between neonatal and adult IFN-γ production does not seem to be related to deficient IL-2 induction by IFN-γ.

Monocyte-derived macrophages from the human neonate are hyporesponsive to activation by IFN-γ a finding that cannot be attributed to lower expression of IFN-γ receptors or decreased affinity of the receptors to their natural ligand on the neonatal cells [18,19]. However in response to IFN-γ significantly decreased STAT-1 phosphorylation was detected in neonatal monocytes [20]. STAT-1 is a convergent point for immunologic stimuli in a macrophage proinflammatory response and the strength of signal through the IFN-γ receptor may influence immune responsiveness. Therefore, these findings raise the possibility that there are important differences in how newborns and adults use STAT-1 to modify immune response to pathogens. Suppressors of cytokine signalling which inhibit JAK-STAT signal transcription pathways may be overexpressed in neonatal monocytes/macrophages [21]. Thus, determining the DNA elements and understanding the transcriptional regulation of cytokine expression in newborns is critical for elucidating the underlying mechanisms of the neonatal bias against Th1 cell differentiation.

Why does then the immune system fail to generate an adequate Th1 type response in newborns? One clue is the hypothesis that during pregnancy there may be a bias towards a Th2 type response and the placenta may synthesize Th2 cytokines to antagonize Th1 responses that could otherwise be harmful to the fetus [22]. Ex utero, the diminished IFN-γ/IL-12 production by neonatal cells may result from the abundance of Th2 cytokines that suppress synthesis of IFN-γ. This possibility is supported by the observation that cord blood T cells produce significantly higher amount of IL-13 than T cells from adults [23].

In conclusion, there appear to be multiple regulatory pathways by which newborns display a biased Th2 immune response. To define the molecular mechanisms involved in these regulatory pathways in newborns vs. adults, and the anatomic sites that are critical to type 2 bias in neonates will be a major task for future research.