Teaching tolerance: Diverse cellular interactions enable healthy maturation

Abstract

The fetal immune system is distinguishable from the adult immune system by a higher degree of tolerance to foreign antigens. This tolerance is important for fetal development within the ‘foreign’ maternal environment, and during birth when barrier surfaces are first colonized by microbiota. Immune responses against the wave of newly colonizing microbiota would cause massive damage to barrier tissues, so neonates need suppressed immune responses and instead rely on maternal antibodies for protection. It is becoming clear that the early‐life establishment of tolerance could impact immune homeostasis and predisposition to autoimmune diseases throughout life. However, it is not well understood how and when perinatal tolerogenic immune responses switch towards adult‐like effector immune responses. Here, we present a new report on the differences between cells from perinatal umbilical cord blood (UCB) and adult peripheral blood mononuclear cells (PBMC), which give mechanistic insights into fetal tolerogenic responses.

Alongside, other mechanisms, a subset of T cells named regulatory T cells (Tregs), have long been described to play an important role in regulating the immune system and establishing tolerance [1]. Tregs express the transcription factor forkhead box protein 3 (Foxp3) and can be generated in the thymus or in the periphery (including the placenta), with peripheral Tregs playing an important role in establishing tolerance [2]. It has previously been reported that UCB and adult blood contain similar frequencies of Foxp3⁺ Tregs, but UCB possesses an increased tendency to develop Tregs. While this difference is known to enable safe fetal development, it remains unclear how fetal Tregs differentiate and what later drives the switch from a perinatal tolerogenic immune response to a more adult‐like immune system.

A paper in this issue sheds light on the mechanisms of fetal Treg differentiation and shows that Treg generation is suppressed in adult blood [3]. It has previously been shown that differences between UCB and PBMC are not confined to T cells but have also been described for antigen‐presenting cells (APCs), a cell type with a pivotal role in the induction of effector T cells and Tregs upon antigen exposure [4]. Lee et al. therefore aimed to understand whether the differences between the perinatal and adult immune systems are caused by the unique nature of perinatal cells and whether specific APCs drive the switch to the adult effector immune response.

In line with previous reports, initial analysis showed similar frequencies of Foxp3⁺ Tregs in naïve UCB and PBMC, but the activation of the blood cells in vitro resulted in increased expression of Foxp3 in UCB compared with that of PBMC. Notably, besides the induction of Foxp3 within CD4⁺ T cells, the authors report the induction of Foxp3 expression in CD8⁺ T cells, which has been reported in peripheral tissue [5] but has not been previously shown in UCB. Further analysis of the in vitro‐generated CD4⁺ and CD8⁺ Tregs revealed that they possessed regulatory function in vitro and in vivo, as shown in a murine graft‐versus‐host disease model.

Tregs are a heterogeneous population and express transcription factors that are also found in T effector cells such as Tbet (Th1 cells), Gata3 (Th2 cells) or Rorγt (Th17 cells). These transcription factors may fine‐tune Treg functions. Tregs expressing the ‘Th17’ transcription factor Rorγt, for instance, are thought to control Th17 immune responses [6]. To characterize the induced Tregs, the authors analysed the co‐expression of Foxp3 with other transcription factors. While adult Tregs predominantly expressed Rorγt and exhibited a Th17‐like phenotype, UCB Tregs expressed a Th1‐type (Tbet) phenotype, which might be linked to the lack of exposure of the fetal immune system to Th17‐inducing microbes such as segmented filamentous bacteria [7].

The authors showed that the predisposition of UCB T cells to differentiate into Tregs was not cell‐intrinsic as T cells isolated from UCB did not show the increased ability to induce Foxp3 expression. This indicated that a different cell type is needed for efficient Treg differentiation. Asking which cell type might be driving Treg differentiation, the authors found that the depletion of CD14⁺ CD36^hi monocytes from the culture led to decreased levels of Tregs. The analysis of these monocytes showed they were a source of retinoic acid through increased ALDH activity and membrane‐bound TGF‐β, which together drive Treg induction [8].

The presence of the CD14⁺ CD36^hi monocytes was identified as the main driver of Treg differentiation in UCB cells. Yet, could the presence of these cells explain the increased Treg differentiation in UCB compared with that in PBMC? Surprisingly, monocytes isolated from PBMC were equally capable of inducing Tregs as UCB monocytes, indicating the inefficient Treg induction in PBMC was not due to functional differences between CD14⁺ CD36^hi monocytes. Next, Lee et al. activated UCB in the presence of granulocytes, monocytes or lymphocytes taken from PBMC and observed reduced Foxp3⁺ Tregs only in the presence of lymphocytes of PBMC. Therefore, the lymphocytes present in PBMC block the differentiation of Foxp3⁺ Tregs from naïve T cells.

This study revealed that the differences between perinatal and adult T cells are not solely cell‐intrinsic but are shaped by surrounding cells. The data show that Treg differentiation between PBMC and UCB T cells can be inhibited by the presence of PBMC lymphocytes, suggesting that these cells might drive the transition from tolerance towards immunogenic responses after birth. Further investigation into which PBMC lymphocytes inhibit Treg induction and how this occurs will provide further exciting results. These findings uncover a mechanism driving the differences between fetal and adult immune responses, with potential relevance to the pathogenesis of childhood diseases as well as Treg function in autoimmune diseases.