Human iPS cell-derived hematopoietic progenitor cells induce T-cell anergy in in vitro-generated alloreactive CD8+ T cells
Human iPS cell-derived hematopoietic progenitor cells induce T-cell anergy in in vitro-generated alloreactive CD8+ T cells
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DOI：
10.1182/blood-2012-11-467753
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发表时间：
2013-06-27
期刊：
影响因子：
20.3
通讯作者：
Zavazava, Nicholas
中科院分区：
文献类型：
--
作者：
Kim, Eun-Mi;Manzar, Gohar;Zavazava, Nicholas
人类诱导多能干细胞（iPSC）已成为多能干细胞的替代来源，可用于组织再生，代替有争议的人类胚胎干细胞。然而，关于iPSC衍生物的免疫学知识仍然是谜。在这里，我们表征了人iPS衍生的CD 34（+）造血祖细胞（HPC）。这些HPC表达主要组织相容性复合体（MHC）I抗原较差，且为MHC-II阴性。有趣的是，它们适度表达非经典HLA-G和HLA-E分子。因此，同种异体反应性HLA-A2特异性细胞毒性T细胞无法识别表达HLA-A2的HPC，而是变得无反应性。随后使用干扰素-γ刺激和提供CD 28共信号转导上调MHC-I导致T细胞活化，证实HPC介导的信号1和2的不良递送介导T细胞无反应性。这些数据首次表明HPC诱导T细胞无反应性，这是iPSC衍生细胞的独特特征，赋予同种异体移植的免疫优势。虽然iPSC是理想的患者定制治疗，预期不需要免疫抑制，但在基因缺陷的情况下，它们的衍生物可用于治疗非组织相容性受体的疾病。
Human induced pluripotent stem cells (iPSCs) have emerged as an alternative source of pluripotent stem cells that can be used for tissue regeneration in place of the controversial human embryonic stem cells. However, immunologic knowledge about iPSC derivatives remains enigmatic. Here, we characterized human iPS-derived CD34(+) hematopoietic progenitor cells (HPCs). These HPCs poorly express major histocompatibility complex (MHC) I antigens and are MHC-II negative. Interestingly, they moderately express non-classical HLA-G and HLA-E molecules. Consequently, alloreactive HLA-A2-specific cytotoxic T cells failed to recognize HLA-A2-expressing HPCs but became anergic. Subsequent upregulation of MHC-I using interferon-gamma stimulation and provision of CD28 cosignaling led to T-cell activation, confirming that poor delivery of signals 1 and 2 by the HPCs mediated T-cell anergy. These data indicate for the first time that HPCs induce T-cell anergy, a unique characteristic of iPSC-derived cells that confers immunologic advantage for allogenic transplantation. Although iPSCs are ideal for patient-tailored treatments with the anticipation that no immunosuppression will be required, in cases of gene defects, their derivatives could be used to treat diseases in nonhistocompatible recipients.