J Immunol. 2026 Nov 2;215(11):vkag301. doi: 10.1093/jimmun/vkag301.
ABSTRACT
CD71+ erythroid cells (CECs) expand in tumor-bearing hosts and suppress antitumor immunity, but the mechanisms underlying their immunoregulatory activity remain incompletely understood. Here, we identify CD39-mediated purine metabolism as a previously unrecognized suppressive pathway used by CECs. In the 4T1 model of triple-negative breast cancer, CD39 was enriched on CD45+ CECs in the spleen, bone marrow, and tumor microenvironment, whereas CD73 was restricted to a smaller subset. Single-cell RNA sequencing mapped Entpd1 and Nt5e expression across CEC subsets and revealed that CD39+ CECs exhibit a broad immunomodulatory transcriptional program. Functionally, CEC-associated CD39 hydrolyzed extracellular ATP to AMP. CD39+ CECs, but not their CD39- counterparts, suppressed T cell proliferation, and A2A adenosine receptor blockade partially restored these responses. Exogenous AMP also impaired T cell effector function through adenosine receptor signaling, supporting a model in which CEC-derived AMP promotes suppression through trans-cellular adenosine production and potentially direct receptor engagement. TGF-β increased CD39 and CD73 expression on CECs in association with SMAD3 activation, suggesting a potential reinforcing regulatory circuit. CD39+ CECs were also detected during early life, pregnancy, and infections, as well as in human bone marrow, indicating relevance beyond cancer. Collectively, these findings identify the adenosinergic axis as an additional component of the multifactorial suppressive program of CECs and reveal a broader mechanism through which erythroid progenitors regulate immunity across physiological and pathological settings.
PMID:43023210 | DOI:10.1093/jimmun/vkag301