Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Sci Transl Med. 2011 Oct 12;3(104):104ra100. doi: 10.1126/scitranslmed.3002949.
T helper 17 (TH17) cells have been shown to contribute to multiple disease systems. However, the functional phenotype and survival pattern of TH17 cells as well as the underlying mechanisms that control TH17 cells have been poorly investigated in humans, significantly hampering the clinical targeting of these cells. Here, we studied human TH17 cells in the pathological microenvironments of graft-versus-host disease, ulcerative colitis, and cancer; TH17 cell numbers were increased in the chronic phase of these diseases. Human TH17 cells phenotypically resembled terminally differentiated memory T cells but were distinct from central memory, exhausted, and senescent T cells. Despite their phenotypic markers of terminal differentiation, TH17 cells mediated and promoted long-term antitumor immunity in in vivo adoptive transfer experiments. Furthermore, TH17 cells had a high capacity for proliferative self-renewal, potent persistence, and apoptotic resistance in vivo, as well as plasticity-converting into other types of TH cells. These cells expressed a relatively specific gene signature including abundant antiapoptotic genes. We found that hypoxia-inducible factor-1α and Notch collaboratively controlled key antiapoptosis Bcl-2 family gene expression and function in TH17 cells. Together, these data indicate that human TH17 cells may be a long-lived proliferating effector memory T cell population with unique genetic and functional characteristics. Targeting TH17-associated signaling pathway would be therapeutically meaningful for treating patients with autoimmune disease and advanced tumor.
辅助性 T 细胞 17（TH17）细胞已被证明与多种疾病系统有关。然而，TH17 细胞的功能表型和存活模式以及控制 TH17 细胞的潜在机制在人类中研究甚少，这极大地阻碍了对这些细胞的临床靶向治疗。在这里，我们研究了移植物抗宿主病、溃疡性结肠炎和癌症等疾病的病理性微环境中的人类 TH17 细胞；这些疾病的慢性阶段 TH17 细胞数量增加。人类 TH17 细胞表型上类似于终末分化的记忆 T 细胞，但与中央记忆、耗竭和衰老 T 细胞不同。尽管它们具有终末分化的表型标记，但在体内过继转移实验中，TH17 细胞介导并促进了长期抗肿瘤免疫。此外，TH17 细胞在体内具有高增殖自我更新能力、强大的持久性和抗凋亡能力，以及转化为其他类型的 TH 细胞的可塑性。这些细胞表达了一种相对特异的基因特征，包括丰富的抗凋亡基因。我们发现，缺氧诱导因子-1α 和 Notch 协同控制 TH17 细胞中关键的抗凋亡 Bcl-2 家族基因表达和功能。总之，这些数据表明，人类 TH17 细胞可能是一种具有独特遗传和功能特征的长寿增殖效应记忆 T 细胞群体。靶向 TH17 相关信号通路对治疗自身免疫性疾病和晚期肿瘤患者具有治疗意义。
