The immunoregulatory function of peripheral blood CD71+ erythroid cells in systemic-onset juvenile idiopathic arthritis

Abstract

CD71+ erythroid cells (CECs) are recognized to have an immunoregulatory function via direct cell–cell interaction and soluble mediators. Circulating CECs appear in newborns or patients with hemolytic and cardiopulmonary disorders. To assess the biological role of CECs in systemic inflammation, we studied the gene expression and function in systemic-onset juvenile idiopathic arthritis (SoJIA). Peripheral blood mononuclear cells of SoJIA patients expressed upregulated erythropoiesis-related genes. It represented the largest expansion of CECs during active phase SoJIA among other inflammatory diseases. Despite the opposing roles of erythropoietin and hepcidin in erythropoiesis, both serum levels were in concert with the amounts of SoJIA-driven CECs. Circulating CECs counts in inflammatory diseases were positively correlated with the levels of C-reactive protein, IL-6, IL-18, or soluble TNF receptors. Co-culture with active SoJIA-driven CECs suppressed secretions of IL-1β, IL-6, and IL-8 from healthy donor monocytes. The top upregulated gene in SoJIA-driven CECs was ARG2 compared with CECs from cord blood controls, although cytokine production from monocytes was suppressed by co-culture, even with an arginase inhibitor. CECs are driven to the periphery during the acute phase of SoJIA at higher levels than other inflammatory diseases. Circulating CECs may control excessive inflammation via the immunoregulatory pathways, partly involving arginase-2.

Potent but transient immunosuppression of T-cells is a general feature of CD71+ erythroid cells

“…We demonstrated that CECs expand in anemic patients and may suppress the production of cytokines by T cells. A small fraction of CD45 + CECs in the peripheral blood of our cohort subject is consistent with a recent report on CECs in systemic juvenile idiopathic arthritis patients 41 . In line with our results, a recent study showed that anemia status influences the blood transcriptome with enrichment of erythrocyte differentiation genes as well as ARG1 in anemic children, but decreased signatures of CD4 + T cell activation and differentiation 42 .…”

“…Recent studies demonstrated that immunomodulatory properties are strong in early-stage CD45 + CECs in contrast to more mature CD45 − CECs that lack these capacities 9 , 10 , 17 , 44 . However, other studies also reported the immunomodulatory role of CD45 − CECs 41 , 45 , which suggests that CD45 alone may not be a reliable marker of immunosuppressive CECs. Here, we showed that human CECs acquire immunomodulatory properties during erythroid differentiation and are the most potent in an early stage characterized by the CD71 high CD235a mid phenotype.…”

Potent but transient immunosuppression of T-cells is a general feature of CD71+erythroid cells

“…We demonstrated that CECs expand in anemic patients and may suppress the production of cytokines by T-cells. A small fraction of CD45 + CECs in the peripheral blood of our cohort subject is consistent with a recent report on CECs in systemic juvenile idiopathic arthritis patients 40 . In line with our results, a recent study showed that anemia status influences the blood transcriptome with enrichment of erythrocyte differentiation genes as well as ARG1 in anemic children, but decreased signatures of CD4 + T-cell activation and differentiation 41 .…”

“…Recent studies demonstrated that immunomodulatory properties are strong in early-stage CD45 + CECs in contrast to more mature CD45 -CECs that lack these capacities 9,10,17,43 . However, other studies also reported the immunomodulatory role of CD45 -CECs 40,44 , which suggests that CD45 alone may not be a reliable marker of immunosuppressive CECs. Here, we showed that human CECs acquire immunomodulatory properties during erythroid differentiation and are the most potent in an early stage characterized by the CD71 high CD235a mid phenotype.…”

Targeting Stress Erythropoiesis Pathways in Cancer

“…Among the immune-associated cells in the tumor microenvironment, macrophages and myeloid-derived suppressor cells play the most prominent immunosuppressive roles ( Fang et al, 2017 ; Dou and Fang, 2021 ). Furthermore, recent studies have brought a renewed focus on the immunomodulatory role of nucleated RBC ( Elahi et al, 2020 ; Kanemasa et al, 2021 ). Apart from the retention of intact nuclei, these erythroid cells display molecular features of an immature erythroid phenotype, such as high expression of the transferrin receptor protein 1 (CD71), and also express genes encoding immune checkpoint molecules, such as CD274 (encoding PD-L1) and CD244 (encoding 2B4) ( Sano et al, 2021 ).…”