Abstract
CD71+ erythroid cells (CECs) have been recently recognized in both neonates and cancer patients as potent immunoregulatory cells. Here, we show that in mice early-stage CECs expand in anemia, have high levels of arginase 2 (ARG2) and reactive oxygen species (ROS). In the spleens of anemic mice, CECs expansion-induced L-arginine depletion suppresses T-cell responses. In humans with anemia, CECs expand and express ARG1 and ARG2 that suppress T-cells IFN-γ production. Moreover, bone marrow CECs from healthy human donors suppress T-cells proliferation. CECs differentiated from peripheral blood mononuclear cells potently suppress T-cell activation, proliferation, and IFN-γ production in an ARG- and ROS-dependent manner. These effects are the most prominent for early-stage CECs (CD71highCD235adim cells). The suppressive properties disappear during erythroid differentiation as more differentiated CECs and mature erythrocytes lack significant immunoregulatory properties. Our studies provide a novel insight into the role of CECs in the immune response regulation.
Highlights
CD71+ erythroid cells (CECs) have been recently recognized in both neonates and cancer patients as potent immunoregulatory cells
Analysis of developmental stages of CECs based on cell size and CD44 levels (Fig. 1e)[16] revealed enrichment of less differentiated CECs in anemic mice compared to non-anemic controls (Fig. 1f and Supplementary Fig. 2c)
We found that CD4+ T cells stimulated with antiCD3/CD28 beads in the presence of CECs showed downregulation of activation markers CD25 and CD69, which was less pronounced for CD62L (Fig. 5a)
Summary
CD71+ erythroid cells (CECs) have been recently recognized in both neonates and cancer patients as potent immunoregulatory cells. CECs differentiated from peripheral blood mononuclear cells potently suppress T-cell activation, proliferation, and IFN-γ production in an ARG- and ROSdependent manner. These effects are the most prominent for early-stage CECs (CD71highCD235adim cells). The authors demonstrated that CECs from mice with acute hemolytic anemia (HA), induced by systemic phenylhydrazine (PHZ) administration, are not immunosuppressive as compared with CECs from tumor-bearing mice[10] This could lead to the conclusion that only CECs in newborns and patients with advanced cancer have robust immunosuppressive properties. We provide evidence that CECs in anemic mice do have immunoregulatory properties, but PHZ used to induce hemolysis affects the mechanisms of immune suppression used by these cells masking their phenotype. We comprehensively elucidate the role of CECs in the regulation of immune response in both mice and humans and demonstrate that immunomodulatory properties of CECs are robust but transient and disappear during their maturation
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