CD71+ Erythroid Cells in Human Neonates Exhibit Immunosuppressive Properties and Compromise Immune Response Against Systemic Infection in Neonatal Mice

Abstract

Newborns are highly susceptible to infectious diseases. The underlying mechanism of neonatal infection susceptibility has generally been related to their under-developed immune system. Nevertheless, this notion has recently been challenged by the discovery of the physiological abundance of immunosuppressive erythroid precursors CD71+erythroid cells (CECs) in newborn mice and human cord blood. Here, as proof of concept, we show that these cells are also abundant in the peripheral blood of human newborns. Although their frequency appears to be more variable compared to their counterparts in mice, they rapidly decline by 4 weeks of age. However, their proportion remains significantly higher in infants up to six months of age compared to older infants. We found CD45 expressing CECs, as erythroid progenitors, were the prominent source of reactive oxygen species (ROS) production in both humans and mice. Interestingly, a higher proportion of CD45+CECs was observed in the spleen versus bone marrow of neonatal mice, which was associated with a higher ROS production by splenic CECs compared to their siblings in the bone marrow. CECs from human newborns suppressed cytokine production by CD14 monocytes and T cells, which was partially abrogated by apocynin in vitro. Moreover, the depletion of CECs in neonatal mice increased the number of activated effector immune cells in their spleen and liver, which rendered them more resistant to Listeria monocytogenes infection. This was evident by a significant reduction in the bacteria load in the spleen, liver and brain of treated-mice compared to the control group, which enhanced their survival rate. Our finding highlights the immunoregulatory processes mediated by CECs in newborns. Thus, such tightly regulated immune system in newborns/infants may explain one potential mechanism for the asymptomatic or mild COVID-19 infection in this population.

Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

“…In contrast to other reports ( Delyea et al., 2018 ; Shahbaz et al., 2018 ), CECs in COVID-19 patients expressed negligible amount of PDL-1/PDL-2 but expressed the V-domain immunoglobulin suppressor of T cell activation ( Figure S1 K). In agreement with our previous reports in other models ( Dunsmore et al., 2017 ; Elahi et al., 2013 ), we found that CECs express significantly higher amounts of arginase II ( Figures 1 F and 1G) and reactive oxygen species (ROS) ( Figures 1 H and 1I) compared with other immune cell lineages, similar to what has been described for their counterparts in human newborns ( Elahi et al., 2020b ), HIV ( Namdar et al, 2019 ), and cancer ( Zhao et al., 2018 ). As a comparison, we measured the expression of ROS in CECs from HIV patients ( Figures S2 A and S2B).…”

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

“…It remains unknown whether EPCs in cancer may induce Treg differentiation, similar to their neonatal counterparts [ 87 ]. Similarly, regardless of a well-established role of EPCs in neonates [ 86 , 94 ], the regulation of myeloid cell response by EPCs in cancer is unknown. Moreover, erythroid cells were reported to produce IL-1β, IL-2, IL-4, IL-6, IFN-γ, and TNF-α [ 306 ]; however, their role in immune regulation by EPCs remains unknown.…”

Sex Matters: Physiological Abundance of Immuno-Regulatory CD71+ Erythroid Cells Impair Immunity in Females

“…CECs mediate their immunosuppressive functions via cell–cell interaction and/or soluble mediators such as Arginase I (Arg I), Arginase II (Arg II) and reactive oxygen species (ROS) ( 15 , 17 , 19 – 22 ). CECs are highly abundant in neonatal mice up to 4-weeks of age regardless of sex and similarly up to 6 months in human newborns ( 18 , 19 , 23 ). Because of the extramedullary erythropoiesis (EE) ( 21 ), CECs expand in the peripheral blood during pregnancy in humans and mice ( 24 , 25 ).…”