Functional unresponsiveness and replicative senescence of myeloid leukemia antigen-specific CD8+ T cells after allogeneic stem cell transplantation.
Functional unresponsiveness and replicative senescence of myeloid leukemia antigen-specific CD8+ T cells after allogeneic stem cell transplantation.
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DOI：
10.1158/1078-0432.ccr-08-3332
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发表时间：
2009-08-01
期刊：
影响因子：
--
通讯作者：
Vonderheide RH
中科院分区：
文献类型：
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作者：
Beatty GL;Smith JS;Reshef R;Patel KP;Colligon TA;Vance BA;Frey NV;Johnson FB;Porter DL;Vonderheide RH
异基因造血干细胞移植（HSCT）对骨髓恶性肿瘤患者的治疗效果部分归因于依赖于供体T淋巴细胞的移植物抗白血病效应。CD 8 + T细胞对MHC I类限制性肿瘤表位的反应，而不仅仅是同种异体抗原，可能有助于介导HSCT后的抗白血病作用，但这些细胞的特异性和功能尚未完全了解。我们研究了异基因造血干细胞移植后髓系白血病患者白血病相关抗原特异性CD 8 + T细胞的多样性、表型和功能潜力。用肽/MHC四聚体文库完成抗原特异性T细胞的筛选。HSCT后缓解的AML或CML患者表现出显著数量的外周血CD 8 + T细胞，其识别来自白血病相关抗原的表位的不同组合。然而，这些细胞不能增殖，释放细胞因子，或去角质反应抗原特异性刺激。早在HSCT后两个月，患者的CD 8 + T细胞主要是CD 28阴性CD 57+，端粒相对较短，与细胞衰老一致。循环白血病特异性CD 8 + T细胞在HSCT后的髓性白血病患者中是突出的，但这些细胞在很大程度上是功能无反应的，最可能是由于复制性衰老。这些发现对于理解移植物抗白血病效应和髓系白血病患者免疫治疗策略的合理设计具有重要意义。
The therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myeloid malignancies has been attributed in part to a graft-versus-leukemia effect that is dependent on donor T lymphocytes. CD8+ T cell responses to MHC class I restricted tumor epitopes, not just allogeneic antigens, may help mediate anti-leukemia effects after HSCT, but the specificity and function of such cells are not completely understood. We examined the diversity, phenotype, and functional potential of leukemia-associated antigen-specific CD8+ T cells in patients with myeloid leukemia following allogeneic HSCT. Screening for antigen-specific T cells was accomplished with a peptide/MHC tetramer library. Patients with AML or CML in remission following HSCT exhibited significant numbers of peripheral blood CD8+ T cells that recognized varying combinations of epitopes derived from leukemia-associated antigens. However, these cells failed to proliferate, release cytokines, or degranulate in response to antigen-specific stimuli. As early as two months after HSCT, CD8+ T cells from patients were predominantly CD28neg CD57+ and had relatively short telomeres, consistent with cellular senescence. Circulating leukemia-specific CD8+ T cells are prominent in myeloid leukemia patients after HSCT, but such cells are largely functionally unresponsive, most likely due to replicative senescence. These findings carry important implications for the understanding of the graft-versus-leukemia effect and for the rationale design of immunotherapeutic strategies for patients with myeloid leukemias.