斯坦福大学Edgar G. Engleman团队近日取得一项新成果。经过不懈努力，他们的论文发现了cDC1s上的促红细胞生成素受体决定免疫耐受。相关论文于2025年12月10日发表于国际顶尖学术期刊《自然》杂志上。

本研究表明，促红细胞生成素受体（EPOR）作为一个关键开关，决定了cDC1s的耐受性功能和抗原特异性T细胞反应的阈值。在总淋巴照射诱导的同种异体移植耐受中，cDC1s上调EPOR的表达，而cDC1s中EPOR的条件敲除会减少抗原特异性诱导和FOXP3⁺调节性T （T_reg）细胞的扩增，从而导致同种异体移植排斥。从机制上说，EPOR促进了脾脏cDC1s对晚期CCR7⁺ cDC1s的代谢成熟，其特征是整合素β8基因（Itgb8）的表达增加，而cDC1s中Itgb8的条件敲除会损害总淋巴细胞辐照与抗胸腺细胞血清诱导的耐受。外周淋巴结的迁移性cDC1s优先表达EPOR，促红细胞生成素可增强其诱导FOXP3⁺ T_reg细胞的能力。

反过来，EPOR的缺失通过上调参与MHC II类和I类介导的抗原呈递、交叉呈递和共刺激的基因，使外周淋巴结迁移和脾CCR7⁺ cDC1s的免疫原性成熟。cDC1s的EPOR缺陷通过增强抗肿瘤T细胞免疫来降低肿瘤生长，特别是增加肿瘤引流淋巴结中前体衰竭的肿瘤抗原特异性CD8⁺ T细胞的产生并支持其在肿瘤内的维持，同时减少瘤内T_reg细胞。靶向cDC1s上的EPOR诱导或抑制T细胞免疫耐受可能具有治疗多种疾病的潜力。

据了解，1型常规树突状细胞（cDC1s）具有独特的胞浆作用和交叉呈递能力，导致抗原特异性T细胞免疫或耐受。然而，cDC1耐受性功能的机制在很大程度上仍然未知。

附：英文原文

Title: Erythropoietin receptor on cDC1s dictates immune tolerance

Author: Zhang, Xiangyue, McGinnis, Christopher S., Yu, Guotao, Chen, Sijie, Zheng, Pingping, Schrch, Christian M., Hiam-Galvez, Kamir J., Reticker-Flynn, Nathan E., Guo, Wenhui, Yao, Winnie, Qiu, Jingtao, Muselman, Alexander, Linde, Ian L., Hickey, John W., Yan, Hao, Tran, Victoria M., Qiu, Wenli, Brichart-Vernos, Delphine, Hirai, Toshihito, Yu, Bo, An, Xiuli, Xiao, Yanling, Paidassi, Helena, Scharschmidt, Tiffany C., Angelo, Michael, Sheppard, Dean, Chi, Hongbo, Satpathy, Ansuman T., Way, Sing Sing, Malissen, Bernard, Strober, Samuel, Engleman, Edgar G.

Issue&Volume: 2025-12-10

Abstract: Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis1 and cross-presenting abilities2, resulting in antigen-specific T cell immunity3 or tolerance4,5,6,7,8. However, the mechanisms that underlie cDC1 tolerogenic function remain largely unknown. Here we show that the erythropoietin receptor (EPOR) acts as a critical switch that determines the tolerogenic function of cDC1s and the threshold of antigen-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance9,10, cDC1s upregulate EPOR expression, and conditional knockout of EPOR in cDC1s diminishes antigen-specific induction and expansion of FOXP3+ regulatory T (Treg) cells, resulting in allograft rejection. Mechanistically, EPOR promotes efferocytosis-induced tolerogenic maturation7,11 of splenic cDC1s towards late-stage CCR7+ cDC1s characterized by increased expression of the integrin β8 gene12 (Itgb8), and conditional knockout of Itgb8 in cDC1s impairs tolerance induced by total lymphoid irradiation plus anti-thymocyte serum. Migratory cDC1s in peripheral lymph nodes preferentially express EPOR, and their FOXP3+ Treg cell-inducing capacity is enhanced by erythropoietin. Reciprocally, loss of EPOR enables immunogenic maturation of peripheral lymph node migratory and splenic CCR7+ cDC1s by upregulating genes involved in MHC class II- and class I-mediated antigen presentation, cross-presentation and costimulation. EPOR deficiency in cDC1s reduces tumour growth by enhancing anti-tumour T cell immunity, particularly increasing the generation of precursor exhausted tumour antigen-specific CD8+ T cells13 in tumour-draining lymph nodes and supporting their maintenance within tumours, while concurrently reducing intratumoural Treg cells. Targeting EPOR on cDC1s to induce or inhibit T cell immune tolerance could have potential for treating a variety of diseases.

DOI: 10.1038/s41586-025-09824-z

Source: https://www.nature.com/articles/s41586-025-09824-z