SARS-CoV-2 infection is associated with lower blood oxygen levels, even in patients without hypoxia requiring hospitalization. This discordance illustrates the need for a more unifying explanation as to whether SARS-CoV-2 directly or indirectly affects erythropoiesis. Here, we show significantly enriched CD71 + erythroid precursors/progenitors in the blood circulation of COVID-19 patients. We found that these cells have distinctive immunosuppressive properties. In agreement, we observed a strong negative correlation between the frequency of these cells with T and B cell proportions in COVID-19 patients. The expansion of these CD71 + erythroid precursors/progenitors was negatively correlated with the hemoglobin levels. A subpopulation of abundant erythroid cells, CD45 + CD71 + cells, co-express ACE2, TMPRSS2, CD147, and CD26, and these can be infected with SARS-CoV-2. In turn, pre-treatment of erythroid cells with dexamethasone significantly diminished ACE2/TMPRSS2 expression and subsequently reduced their infectivity with SARS-CoV-2. This provides a novel insight into the impact of SARS-CoV-2 on erythropoiesis and hypoxia seen in COVID-19 patients.

Survival of the allogeneic pregnancy depends on the maintenance of immune tolerance to paternal alloantigens at the fetomaternal interface. Multiple localized mechanisms contribute to the fetal evasion from the mother's immune rejection as the fetus is exposed to a wide range of stimulatory substances such as maternal alloantigens, microbes and amniotic fluids. In this article, we demonstrate that CD71 erythroid cells are expanded at the fetomaternal interface and in the periphery during pregnancy in both humans and mice. These cells exhibit immunosuppressive properties, and their abundance is associated with a Th2 skewed immune response, as their depletion results in a proinflammatory immune response at the fetomaternal interface. In addition to their function in suppressing proinflammatory responses in vitro, maternal CD71 erythroid cells inhibit an aggressive allogeneic response directed against the fetus such as reduction in TNF-α and IFN-γ production through arginase-2 activity and PD-1/programmed death ligand-1 (PDL-1) interactions. Their depletion leads to the failure of gestation due to the immunological rejection of the fetus. Similarly, fetal liver CD71 erythroid cells exhibit immunosuppressive activity. Therefore, immunosuppression mediated by CD71 erythroid cells on both sides (mother/fetus) is crucial for fetomaternal tolerance. Thus, our results reveal a previously unappreciated role for CD71 erythroid cells in pregnancy and indicate that these cells mediate homeostatic immunosuppressive/immunoregulatory responses during pregnancy.

of the experiments and analyzed the data. L.X. performed some of the experiments and analyzed the data. W.S. (a clinician scientist in critical care medicine and infectious disease) identified and recruited patients for the study. M.O., a clinician scientist (Rheumatologist), contributed in patients' recruitment. N.B. performed the ELISAs. D.R. contributed in clinical data collection. S.M. and E.P.R. assisted in blood processing and experimental setups. J.W. as a clinician scientist (Oncologist) provided advice. S.E. conceptualized, designed the study, secured funding and resources, performed some of the experiments, assisted in data analysis, designed figures, supervised all of the research, and wrote the manuscript.

Infant’s immune system cannot control infection or respond to vaccination as efficiently as older individuals, a phenomenon that has been attributed to immunological immaturity. Recently, we challenged this notion and proposed the presence of actively immunosuppressive and physiologically enriched CD71+ erythroid cells in neonates. Here we utilized Bordetella pertussis, a common neonatal respiratory tract pathogen, as a proof of concept to investigate the role of these cells in adaptive immunity. We observed that CD71+ cells have distinctive immunosuppressive properties and prevent recruitment of immune cells to the mucosal site of infection. CD71+ cells ablation unleashed induction of B. pertussis-specific protective cytokines (IL-17 and IFN-γ) in the lungs and spleen upon re-infection or vaccination. We also found that CD71+ cells suppress systemic and mucosal B. pertussis-specific antibody responses. Enhanced antigen-specific adaptive immunity following CD71+ cells depletion increased resistance of mice to B. pertussis infection. Furthermore, we found that human cord blood CD71+ cells also suppress T and B cell functions in vitro. Collectively, these data provide important insight into the role of CD71+ erythroid cells in adaptive immunity. We anticipate our results will spark renewed investigation in modulating the function of these cells to enhance host defense to infections in newborns.

the experiments, analyzed the data, designed some of the experiments, and wrote the first draft. G.D. performed ImageStream studies. P.K. performed qPCR studies. L.X. assisted in data analysis and performed a few experiments. S.H. contributed in HIV patients recruitment. S.E. conceived the original idea, designed and supervised all of the research, assisted in data analysis, and wrote the manuscript.