During development, the fetus encounters many potentially immunostimulatory molecules, including semi-allogeneic maternal antigens, dietary components and microbial antigens, and it has been unclear how its immune system responds to these antigens. Florent Ginhoux and colleagues now report that by the second trimester, the developing fetus has all of the main antigen-presenting cell (APC) types that are present in adults and that fetal dendritic cells (DCs) can sense pathogen components and stimulate T cell responses. However, compared with adult DCs, fetal DCs seem to be more potent in inducing tolerogenic immune responses.
The authors initially characterized the different APC types that are found in the human fetus using techniques that had previously been used to describe adult APC populations. By 13 weeks estimated gestational age (EGA), they could identify CD14+ monocytes and macrophages, plasmacytoid DCs, conventional type 1 DCs (cDC1s) and cDC2s in the fetal spleen, skin, thymus and lungs. They focused on characterizing fetal cDCs in more detail, and found that tissue imprinting is important for shaping the phenotypes of fetal cDC1 and cDC2 populations. Indeed, the phenotypes of many tissue-specific cDCs were conserved between adults and fetuses.
Interestingly, cDCs from the fetal gut had a more activated phenotype than cDCs from other fetal tissues, as determined by increased expression of costimulatory molecules and CC-chemokine receptor 7 (CCR7), which promotes trafficking to lymph nodes. In agreement with this, the authors identified migratory DCs in the fetal mesenteric lymph nodes at 16 weeks EGA. Further studies suggested that fetal DCs begin to migrate from the skin and gut at around 16 weeks EGA.
The authors next compared the responses of adult and fetal cDCs to activating stimuli. They found that splenic cDCs from adults or from fetuses of 17–22 weeks EGA produced similar amounts of pro- inflammatory cytokines in response to stimulation with Toll-like receptor (TLR) ligands. In addition, both adult and fetal cDCs stimulated comparable levels of T cell proliferation in mixed lymphocyte reactions using allogeneic adult T cells. Therefore, fetal cDCs are capable of sensing pathogens and stimulating T cell responses by 17 weeks EGA. However, fetal cDCs generated higher frequencies of FOXP3+ regulatory T (Treg) cells in co-cultures with allogeneic adult T cells, and these induced Treg cells showed suppressive activity in vitro. Allogeneic T cells co-cultured with fetal cDCs also produced lower levels of pro-inflammatory cytokines and increased amounts of IL-4 compared with allogeneic T cells co-cultured with adult cDCs.
“fetal cDCs inhibited TNF production by T cells in an arginase 2-dependent manner”
Gene expression analyses identified several genes that are associated with inflammation or immune suppression that were differentially regulated between fetal and adult cDCs. Of note, fetal cDCs had increased expression of ARG2 (which encodes arginase 2, an enzyme that depletes the tissue of the L-arginine that is required for tumour necrosis factor (TNF) production). Previous work has shown that arginase 2 is important for regulating TNF activity in the neonate and, in keeping with this, fetal cDCs inhibited TNF production by T cells in an arginase 2-dependent manner. However, the ability of fetal cDCs to induce Treg cell development and suppress T cell production of other pro-inflammatory cytokines did not require arginase 2, suggesting that cDCs use other mechanisms to regulate these responses.
These findings indicate that fetal DCs can respond to immunostimulatory challenges, but suggest that in the steady state they are biased towards the suppression of inflammation. Future studies should help to clarify the additional mechanisms that are used by fetal DCs to induce Treg cell development and suppress TNF production and, importantly, how TLR stimulation is able to override such immunosuppressive pathways during intrauterine infections.
McGovern, N. et al. Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2. Nature 546, 662–666 (2017)