Page 21 - Haematologica - Vol. 105 n. 6 - June 2020

Immunoregulatory functions of CD71+ erythroid cells
CEC express arginase-2, whose activity is essential for the cells’ immunosuppressive properties.9 The presence of CEC was found to be associated with increased neona- tal susceptibility to infection.9 However, CEC-mediated susceptibility to infection was counterbalanced by these cells’ protective role against aberrant immune cell activa- tion in the intestine, allowing swift colonization by microbial communities after parturition.9 This was shown by increased immune cell activation and produc- tion of pro-inflammatory cytokines [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] by antigen-presenting cells in the intestine when CEC were partially depleted in wildtype compared to germ-free mice.9 In addition, fol- lowing studies in a murine model of whooping cough, it was reported that CEC impaired innate immune respons- es against Bordetella pertussis infection.10 Specifically, depletion of CEC unleashed an innate immune response characterized by enhanced production of protective cytokines [interferon (IFN)-γ, TNF-α, and IL-12] and resulted in the recruitment of natural killer cells and anti- gen-presenting cells in the lungs of neonatal mice, which restored resistance to B. pertussis infection. In contrast, neonatal CEC adoptively transferred into adult recipients by intravenous injection impaired the adults’ innate immune response against B. pertussis infection.10 Moreover, the enzymatic activity of arginase-2 secreted by CEC inhibited phagocytosis of B. pertussis in vitro.10 These observations challenged the notion of neonatal susceptibility to infection being due to intrinsic defects of immune cells, and instead highlighted active immune suppression mediated by the abundance of CEC in the newborn. These findings provided additional support to the novel concept in neonatal immunology that immuno- suppression is essential to dampen costly robust immune responses in newborns. Further studies demonstrated that CEC hindered adaptive cellular and humoral immune responses to infection with B. pertussis and vac- cination against this pathogen in neonatal mice. Depletion of CEC before vaccination resulted in a sub- stantial increase in the induction of antigen-specific pro- tective cytokines (IFN-γ and IL-17) and antibodies (IgA and IgG) against B. pertussis.12 Similarly, the ablation of CEC before a primary infection resulted in more robust, protective immunity following re-infection with B. pertus- sis in neonatal mice.12 These observations suggest that the accumulation of CEC in the periphery could have detri- mental effects on both the innate and adaptive immune responses to pathogens. Furthermore, CEC from human cord blood and placenta have immunosuppressive effects following stimulation with different bacterial ligands or anti-CD3/CD28 in vitro.9,12,13 In a complementary study, pre-term labor-derived human cord blood CEC were shown to participate in the suppression of CD4+ and CD8+ T-cell proliferation and modulate cytokine produc- tion by antigen-presenting cells in the presence of heat- killed Listeria monocytogenes.14 These observations raised the possibility that CEC might have immunomodulatory rather than immunosuppressive properties, leading to enhanced pro-inflammatory cytokine production under specific circumstances (e.g., CEC from pre-term versus full-term cord blood). Although CEC impair both innate and adaptive immune responses against pathogens in the neonate, their crucial role in the host’s adaptation to microbial communities has lifelong benefits and deserves appreciation (Figure 1).
Future research should be directed at understanding the cross-talk between CEC and microbial communities to determine any therapeutic benefit in human newborns. Such novel studies will establish the scientific framework for more in-depth translational studies in the future.
Immunological benefits of extramedullary erythropoiesis in pregnancy and gut homeostasis
A good pregnancy outcome requires selective silencing of maternal immune effector cells against the father’s fetal alloantigens.15,16 The fetus is antigenically similar to a semi-allogeneic transplant, with the risk of immunologi- cal rejection. As such, the mother’s immune response dur- ing gestation requires tolerance to alloantigens, prevent- ing potentially damaging immune responses that may result in abortion or preterm delivery.17 The maintenance of pregnancy does, therefore, represent a major challenge for the maternal immune system, since it has to tolerate a semi-allogeneic fetus and at the same time protect both the mother and the fetus against potential pathogens. Several mechanisms have been reported to be involved in blocking the immunological rejection of the fetus,18,19 including those modified by CEC. During pregnancy, especially after mid-gestation, the total red blood cell count increases to meet the increased demand for blood supply by the mother and the fetus. The normal range of erythropoietin concentration in pregnant women is var- ied, although erythropoietin concentration rises as the demand for blood supply increases.20 This high level of erythropoietin, alongside other factors, such as 27- hydroxycholesterol, the cholesterol metabolite, which induces hematopoietic stem cell mobilization through the estrogen receptor α, is required for EE formation during gestation.21 In concert with estradiol, 27-hydroxycholes- terol promotes EE by regulating estrogen receptor α func- tion in hematopoietic stem cell mobilization. In agree- ment with this concept, Delyea et al. found physiological expansion of CEC in the spleen and peripheral blood of an allogeneic mouse model of pregnancy.22 Although a moderate expansion of CEC was observed in syngeneic pregnancy, it was significantly lower than that in the allo- geneic mice.22 This suggests a potential role for CEC in response to alloantigens. In support of these hypotheses, an abundance of CEC was found at the feto-maternal interface during pregnancy.22 Maternal CEC, like the neonatal CEC, expressed arginase-2 and activity of this enzyme was required for the cells’ inhibitory effect against the aggressive allogeneic response at the feto- maternal interface. These CEC from the spleen and pla- cental tissues of pregnant mice, unlike neonatal CEC, expressed substantial levels of programmed death-1/2 lig- ands (PDL-1/PDL-2) and subsequently suppressed PD-1- expressing T cells at the feto-maternal interface.22 Furthermore, the ablation of CEC in allogeneic mice skewed the immune response toward a Th1 response characterized by upregulation of inflammatory cytokines and chemokines (e.g. TNF-α and IFN-γ, IL-6 and CXCL-1) resulting in fetal resorption.22 Similarly, expansion of CEC was observed in the peripheral blood of pregnant women in the second and third trimesters of pregnancy.13 CEC from either peripheral blood or cord blood/placental tis-
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