Neonatal follicular Th cell responses are impaired and modulated by IL-4.

Newborns are characterized by poor responses to vaccines. Defective B cell responses and a Th2-type polarization can account for this impaired protection in early life. We in this study investigated the generation of follicular Th (TFH) cells, involved in the development of Ab response and germinal center reaction, upon vaccination in neonates. We showed that, compared with adults, Ab production, affinity maturation, and germinal center formation were reduced in neonates immunized with OVA-aluminum hydroxide. Although this vaccination induced CD4(+) CXCR5(+) PD-1(+) TFH cells in newborns, their frequency, as well as their Bcl6 expression and IL-21 and IL-4 mRNA induction, was decreased in early life. Moreover, neonatal TFH cells were mainly localized in interfollicular regions of lymphoid tissues. The prototypic Th2 cytokine IL-4 was found to promote the emergence and the localization in germinal centers of neonatal TFH cells, as well as the neonatal germinal center reaction itself. In addition, IL-4 dampened expression of Th17-related molecules in neonatal TFH cells, as TFH cells from immunized IL-4-deficient neonates displayed enhanced expression of RORγt and IL-17. This Th17-like profile correlated with an increased secretion of OVA-specific IgG2a. Our study thus suggests that defective humoral immunity in early life is associated with limited and IL-4-modulated TFH cell responses.

Unbalanced Neonatal CD4(+) T-Cell Immunity.

In comparison to adults, newborns display a heightened susceptibility to pathogens and a propensity to develop allergic diseases. Particular properties of the neonatal immune system can account for this sensitivity. Indeed, a defect in developing protective Th1-type responses and a skewing toward Th2 immunity characterize today the neonatal T-cell immunity. Recently, new findings concerning Th17, regulatory helper T-cell, and follicular helper T-cell subsets in newborns have emerged. In some circumstances, development of effector inflammatory Th17-type responses can be induced in neonates, while differentiation in regulatory T-cells appears to be a default program of neonatal CD4(+) T-cells. Poor antibody production, affinity maturation, and germinal center reaction in vaccinated neonates are correlated with a limiting expansion of TFH lymphocytes. We review herein the factors accounting for and the implications of the unbalanced neonatal helper T-cell immunity.

Th2 alloimmunity counteracts Th17-type response in the neonatal establishment of lymphoid chimerism.

The neonatal period of life is described as particularly susceptible to develop tolerance. This status of neonatal tolerance has been studied for decades since the discovery that semiallogeneic spleen cells inoculated at birth can induce donor-type graft acceptance. The host neonatal T­cell compartment that may account for this propensity to develop tolerance is mostly characterized by a Th2-type polarized response and a default in the cytotoxic T lymphocyte (CTL) functions that allow the establishment of lymphoid chimerism and promote donor-type graft survival. We highlighted a new role of alloreactive Th17 cells as a critical barrier to neonatal tolerance that prevents this lymphoid chimerism and further demonstrated that the Th2 immune deviation is essential to control this Th17-type response. We discuss here the potential impact of breaking the tolerizing effects of exposure of the developing offspring to alloantigens in the induction of Th17-type immunity.