Experimental Immunology Unit, Division of Immunology, Transplantation, and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milano, Italy.
J Immunol. 2011 Apr 1;186(7):4490-9. doi: 10.4049/jimmunol.1003748. Epub 2011 Feb 25.
Immune reconstitution plays a crucial role on the outcome of patients given T cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (hHSCT) for hematological malignancies. CD1d-restricted invariant NKT (iNKT) cells are innate-like, lipid-reactive T lymphocytes controlling infections, cancer, and autoimmunity. Adult mature iNKT cells are divided in two functionally distinct CD4(+) and CD4(-) subsets that express the NK receptor CD161 and derive from thymic CD4(+)CD161(-) precursors. We investigated iNKT cell reconstitution dynamics in 33 pediatric patients given hHSCT for hematological malignancies, with a follow-up reaching 6 y posttransplantation, and correlated their emergence with disease relapse. iNKT cells fully reconstitute and rapidly convert into IFN-γ-expressing effectors in the 25 patients maintaining remission. CD4(+) cells emerge earlier than the CD4(-) ones, both displaying CD161(-) immature phenotypes. CD4(-) cells expand more slowly than CD4(+) cells, though they mature with significantly faster kinetics, reaching full maturation by 18 mo post-hHSCT. Between 4 and 6 y post-hHSCT, mature CD4(-) iNKT cells undergo a substantial expansion burst, resulting in a CD4(+)<CD4(-) NKT cell ratio similar to that found in healthy adults. In contrast with patients maintaining remission, iNKT cells failed to reconstitute in all eight patients experiencing disease relapse. These findings define the peripheral dynamics of human iNKT cells and suggest a contribution of these cells to maintain remission, possibly via early IFN-γ provision. Adoptive transfer of donor-derived iNKT cells into HLA-haploidentical patients failing to reconstitute these cells might represent a novel therapeutic option to prevent leukemia recurrence.
免疫重建对接受 T 细胞耗竭 HLA 单倍体相合造血干细胞移植（hHSCT）治疗血液系统恶性肿瘤的患者的结局起着至关重要的作用。CD1d 限制性不变自然杀伤 T（iNKT）细胞是先天样、脂质反应性 T 淋巴细胞，可控制感染、癌症和自身免疫。成人成熟的 iNKT 细胞分为两个功能不同的 CD4(+)和 CD4(-)亚群，它们表达 NK 受体 CD161，源自胸腺 CD4(+)CD161(-)前体。我们研究了 33 例接受 hHSCT 治疗血液系统恶性肿瘤的儿科患者的 iNKT 细胞重建动态，随访时间达到移植后 6 年，并将其出现与疾病复发相关联。在 25 例维持缓解的患者中，iNKT 细胞完全重建并迅速转化为 IFN-γ 表达效应物。CD4(+)细胞比 CD4(-)细胞更早出现，两者均表现出不成熟的 CD161(-)表型。CD4(-)细胞的扩增速度比 CD4(+)细胞慢，但它们的成熟速度明显更快，在 hHSCT 后 18 个月达到完全成熟。在 hHSCT 后 4 至 6 年，成熟的 CD4(-)iNKT 细胞经历了一次实质性的扩增爆发，导致 CD4(+)<CD4(-)NKT 细胞比例与健康成年人相似。与维持缓解的患者不同，所有 8 例疾病复发的患者均未能重建 iNKT 细胞。这些发现定义了人类 iNKT 细胞的外周动态，并提示这些细胞可能通过早期 IFN-γ 提供来维持缓解。将供体来源的 iNKT 细胞过继转移到未能重建这些细胞的 HLA 单倍体相合患者中，可能代表预防白血病复发的一种新的治疗选择。
