Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation
Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation
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DOI：
10.1182/blood-2014-11-608406
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发表时间：
2015-04-30
期刊：
影响因子：
20.3
通讯作者：
Lugli, Enrico
中科院分区：
文献类型：
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作者：
Roberto, Alessandra;Castagna, Luca;Lugli, Enrico
同种异体移植后的早期T细胞重建取决于移植物过继转移的T细胞的持久性和功能。移植后环磷酰胺（pt-Cy）可有效防止未处理移植物的同种异体反应，但其对随后免疫重建的影响仍不确定。在这里，我们发现T记忆干细胞（TSCM）在临床前模型中表现出优越的重建能力，在单倍体移植与pt-Cy结合后的早期，在效应细胞扩增之前，是最丰富的循环T细胞群。移植的幼稚记忆细胞，而不是TSCM或传统记忆细胞优先在环磷酰胺中存活，这表明移植后的TSCM起源于幼稚前体。此外，对外源抗原和自身/肿瘤抗原具有特异性的供体幼稚T细胞在宿主体内持续存在，并通过分化为效应器促进外周重构。同样，病原体特异性记忆T细胞产生可检测的回忆反应，但只有在同源抗原存在的情况下。因此，我们在抗原特异性水平上定义了pt-Cy后t细胞重构的细胞基础，并提出在临床环境中探索天然来源的TSCM以克服免疫缺陷。
Early T-cell reconstitution following allogeneic transplantation depends on the persistence and function of T cells that are adoptively transferred with the graft. Posttransplant cyclophosphamide (pt-Cy) effectively prevents alloreactive responses from unmanipulated grafts, but its effect on subsequent immune reconstitution remains undetermined. Here, we show that T memory stem cells (TSCM), which demonstrated superior reconstitution capacity in preclinical models, are the most abundant circulating T-cell population in the early days following haploidentical transplantation combined with pt-Cy and precede the expansion of effector cells. Transferred naive, but not TSCM or conventional memory cells preferentially survive cyclophosphamide, thus suggesting that posttransplant TSCM originate from naive precursors. Moreover, donor naive T cells specific for exogenous and self/tumor antigens persist in the host and contribute to peripheral reconstitution by differentiating into effectors. Similarly, pathogen-specific memory T cells generate detectable recall responses, but only in the presence of the cognate antigen. We thus define the cellular basis of T-cell reconstitution following pt-Cy at the antigen-specific level and propose to explore naive-derived TSCM in the clinical setting to overcome immunodeficiency.