Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies^1,2. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena³. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory⁴. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis^3,5,6. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer⁵. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.

免疫系统衰老的特点是淋巴细胞生成和适应性免疫减少，以及炎症和骨髓病变增加^1,2。自我更新造血干细胞 (HSC) 群体中与年龄相关的变化被认为是这些现象的基础³。在青年时期，具有平衡的淋巴和骨髓细胞输出的 HSC（bal-HSC）比具有偏向骨髓的输出的 HSC（my-HSC）占主导地位，从而促进启动适应性免疫反应所需的淋巴细胞生成，同时限制骨髓细胞的产生，它可以促炎⁴。衰老与 my-HSC 比例增加相关，导致淋巴细胞生成减少和骨髓生成增加^3,5,6。 bal-HSC 的转移会产生丰富的淋巴和骨髓细胞，这是二次转移后保留的稳定表型； my-HSC 在二次转移后也保留其生产模式⁵。这两个子集的起源和潜在的相互转化仍不清楚。如果它们在出生后是独立的子集，那么通过消除老年小鼠中的 my-HSC 来逆转衰老表型是可能的。在这里，我们证明，在老年小鼠中，抗体介导的 my-HSC 消耗可以恢复更年轻的免疫系统的特征，包括增加常见淋巴细胞祖细胞、幼稚 T 细胞和 B 细胞，同时减少与年龄相关的免疫衰退标志物。老年小鼠 my-HSC 的消耗可改善对病毒感染的初级和次级适应性免疫反应。这些发现可能与理解和干预由于 my-HSC 主导造血系统而加剧或引起的疾病有关。