Erythroid progenitors exhibit non-canonical cellular response to double-stranded DNA 2243743

Abstract Introduction Erythroid cells, like classical immune cells, arise from hematopoietic stem cells, yet their immune potential remains largely unexplored. Methods To investigate their role in immunity, we analyzed single cell RNA-seq data from human umbilical cord blood and discovered that erythroid progenitors express key components of the cytosolic DNA-sensing cGAS-STING pathway. We confirmed constitutive expression and canonical localization of these genes in human umbilical cord blood-derived erythroid progenitor (HUDEP-2) cells. Results HUDEP-2 cells are a unique model to probe the DNA-sensing capacity of erythroid progenitors due to their doxycycline-inducible expression of HPV-E7, which degrades STING. Surprisingly, despite degradation of STING, HUDEP-2 cells mounted a robust transcriptional response to transfection with dsDNA. These changes did not align with a type I interferon response, but instead pointed to a non-canonical NFκB-dependent activation. Upregulated genes were enriched for immune cell differentiation pathways, including myeloid-specific transcription factors. Conclusion Our results suggest that erythroid progenitors are capable of sensing exogenous DNA independently of STING and subsequently initiating a non-canonical, interferon-independent immune program that may influence lineage fate decisions. These findings challenge the assumption that erythroid progenitors are immunologically inert and instead suggest a role for erythroid cells in mediating innate antiviral immunity and hematopoiesis. Funding Source NIH R15AI188361, NIH K12GM081259, American Heart Association 23POST1013585, NIH 5T32DK007780, Burroughs Wellcome Fund 2022 Next Gen Pregnancy Initiative Award Topic Categories Hematopoiesis and Immune System Development (HEM)