Highlights d Patients with severe COVID-19 accumulate HLA-DR Low monocytes and immature neutrophils in blood/lungs d Calprotectin level positively correlates with neutrophil count and disease severity d Loss of non-classical monocytes could identify high risk of severe COVID-19
Newborns are highly susceptible to infection. The underlying mechanism of neonatal infection susceptibility has generally been associated with neonatal immune cell immaturity. In this study, we challenged this notion and built upon our recent discovery that neonates are physiologically enriched with erythroid TER119CD71 cells (Elahi et al. 2013. 504: 158-162). We have used, a common neonatal respiratory tract infection, as a proof of concept to investigate the role of these cells in newborns. We found that CD71 cells have distinctive immune-suppressive properties and suppress innate immune responses against infection. CD71 cell ablation unleashed innate immune response and restored resistance to infection. In contrast, adoptive transfer of neonatal CD71 cells into adult recipients impaired their innate immune response to infection. Enhanced innate immune response to was characterized by increased production of protective cytokines IFN-γ, TNF-α, and IL-12, as well as recruitment of NK cells, CD11b, and CD11c cells in the lung. Neonatal and human cord blood CD71 cells express arginase II, and this enzymatic activity inhibits phagocytosis of in vitro. Thus, our study challenges the notion that neonatal infection susceptibility is due to immune cell-intrinsic defects and instead highlights active immune suppression mediated by abundant CD71 cells in the newborn. Our findings provide additional support for the novel theme in neonatal immunology that immunosuppression is essential to dampen robust immune responses in the neonate. We anticipate that our results will spark renewed investigation in modulating the function of these cells and developing novel strategies for enhancing host defense to infections in newborns.
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.
Background and Aims: CD71 + erythroid cells are enriched during pregnancy with immuno suppressive properties. We investigated the frequency and functionality of CD71 + erythroid cells in peripheral blood, cord blood, and placenta of inflammatory bowel disease [IBD] patients versus healthy controls [HCs]. We aimed to determine their role in IBD pathogenesis during pregnancy. Methods: Peripheral blood was collected at preconception, the first, second and third trimesters, and postpartum. Cord blood and placental tissues were collected at the time of birth. Cells from different specimens were subjected to immunephenotyping and functional assays. CD71 + erythroid cells were purified for quantitative polymerase chain reaction [qPCR] analysis. Using an allogeneic mouse model of pregnancy, the effects of CD71 + erythroid cells depletion on intestinal homeostasis and dysbiosis was studied. Results: IBD patients had lower CD71 + erythroid cells during pregnancy compared with HCs. Placenta and cord blood CD71 + erythroid cells from IBD patients exhibited impaired functionality and expressed lower inhibitory molecules including VISTA, TGFβ, and reactive oxygen species [ROS]. Lower CD71 + erythroid cells were correlated with reduced regulatory T cells and increased immuneactivation in IBD patients. Depletion of CD71 + erythroid cells in an allogeneic pregnancy model resulted in upregulation of TLRs, IL6, and CXCL1, and enhanced production of TNFα, in intestinal tissues. In contrast, TGF β gene expression was reduced. Excessive inflammatory response in the gut [e.g. TNFα] affects intestinal integrity and CD71 + erythroid cells impact on the gut's bacterial composition. Conclusions: Reduced frequency and/or impaired functionality of CD71 + erythroid cells during pregnancy may predispose IBD patients to a more proinflammatory milieu in their gastrointestinal tract, characterised by lower Tregs, higher IL6, and TNFα, and dysbiosis.
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.
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