Dubouchet Laetitia, Todorov Helena, Seurinck Ruth, Vallet Nicolas, Van Gassen Sofie, Corneau Aurélien, Blanc Catherine, Zouali Habib, Boland Anne, Deleuze Jean-François, Ingram Brian, de Latour Regis Peffault, Saeys Yvan, Socié Gérard, Michonneau David
Université de Paris, INSERM U976, F-75010 Paris, France.
Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, 9052 Ghent, Belgium.
Sci Transl Med. 2022 Feb 23;14(633):eabg3083. doi: 10.1126/scitranslmed.abg3083.
The mechanisms underlying operational tolerance after hematopoietic stem cell transplantation in humans are poorly understood. We studied two independent cohorts of patients who underwent allogeneic hematopoietic stem cell transplantation from human leukocyte antigen-identical siblings. Primary tolerance was associated with long-lasting reshaping of the recipients' immune system compared to their healthy donors with an increased proportion of regulatory T cell subsets and decreased T cell activation, proliferation, and migration. Transcriptomics profiles also identified a role for nicotinamide adenine dinucleotide biosynthesis in the regulation of immune cell functions. We then compared individuals with operational tolerance and nontolerant recipients at the phenotypic, transcriptomic, and metabolomic level. We observed alterations centered on CD38-activated T and B cells in nontolerant patients. In tolerant patients, cell subsets with regulatory functions were prominent. RNA sequencing analyses highlighted modifications in the tolerant patients' transcriptomic profiles, particularly with overexpression of the ectoenzyme (encoding CD73), which could counterbalance CD38 enzymatic functions by producing adenosine. Further, metabolomic analyses suggested a central role of androgens in establishing operational tolerance. These data were confirmed using an integrative approach to evaluating the immune landscape associated with operational tolerance. Thus, balance between a CD38-activated immune state and CD73-related production of adenosine may be a key regulator of operational tolerance.
人类造血干细胞移植后产生操作耐受的潜在机制目前仍知之甚少。我们研究了两组独立的患者队列，这些患者均接受了来自人类白细胞抗原匹配同胞的异基因造血干细胞移植。与健康供体相比，原发性耐受与受者免疫系统的长期重塑有关，调节性T细胞亚群比例增加，T细胞活化、增殖和迁移减少。转录组学分析还确定了烟酰胺腺嘌呤二核苷酸生物合成在免疫细胞功能调节中的作用。然后，我们在表型、转录组和代谢组水平上比较了具有操作耐受的个体和无耐受的受者。我们观察到，在无耐受患者中，以CD38激活的T细胞和B细胞为中心的改变。在耐受患者中，具有调节功能的细胞亚群较为突出。RNA测序分析突出了耐受患者转录组谱的变化，特别是胞外酶（编码CD73）的过表达，其可通过产生腺苷来抵消CD38的酶促功能。此外，代谢组学分析表明雄激素在建立操作耐受中起核心作用。这些数据通过综合评估与操作耐受相关的免疫格局的方法得到了证实。因此，CD38激活的免疫状态与CD73相关的腺苷产生之间的平衡可能是操作耐受的关键调节因子。
