Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Mol Immunol. 2018 Jul;99:145-153. doi: 10.1016/j.molimm.2018.05.011. Epub 2018 May 18.
The rapid antitumor cytokine production and direct cytotoxicity confer invariant NKT (iNKT) cells ideal candidates for cancer therapy. However, the therapeutic potential of iNKT cells in T-cell malignant diseases remains elusive, as antigen presentation by T cells (T-T presentation) has been suggested to induce hyporesponsiveness of iNKT cells. In this study, we found discrepancies in iNKT cell responses against two T cell-origin cell lines (Jurkat and Molt-4). Human iNKT cells exhibited more intensive cytotoxicity and less efficient cytokine production in response to Fas-bearing Jurkat cells than those to the Fas-negative tumor cells (Molt-4 and myeloid-derived K562). The imbalanced cytokine/cytotoxicity responses of iNKT cells against Jurkat cells were CD1d-dependent and relied mostly on Fas/FasL interaction. The impairment in cytokine production could be overcome by Fas/FasL blocking antibodies and exogenous IL-2. Elevated CD1d levels as well as CD1d and Fas co-localization were found in T-cell lymphomas. However, defects in frequency and function of circulating iNKT cells were observed in the patients, which could be partly rescued by exogenous IL-2. Collectively, the Fas/FasL-dependent aberrant iNKT cell responses and the reversibility of the defects suggest the distinct iNKT cell manipulation in CD1d- and Fas-bearing T cell malignancies.
快速产生抗肿瘤细胞因子和直接细胞毒性使不变自然杀伤 T(iNKT)细胞成为癌症治疗的理想候选者。然而，iNKT 细胞在 T 细胞恶性疾病中的治疗潜力仍不清楚，因为 T 细胞的抗原呈递（T-T 呈递）被认为会诱导 iNKT 细胞的低反应性。在这项研究中，我们发现 iNKT 细胞对两种 T 细胞来源的细胞系（Jurkat 和 Molt-4）的反应存在差异。人类 iNKT 细胞对 Fas 阳性 Jurkat 细胞的细胞毒性和细胞因子产生反应比 Fas 阴性肿瘤细胞（Molt-4 和髓系来源的 K562）更强烈。iNKT 细胞对 Jurkat 细胞的不平衡细胞因子/细胞毒性反应依赖于 CD1d，主要依赖于 Fas/FasL 相互作用。Fas/FasL 阻断抗体和外源性 IL-2 可克服细胞因子产生的损伤。在 T 细胞淋巴瘤中发现 CD1d 水平升高以及 CD1d 和 Fas 共定位。然而，在患者中观察到循环 iNKT 细胞的频率和功能缺陷，外源性 IL-2 可部分挽救这些缺陷。总之，Fas/FasL 依赖性异常 iNKT 细胞反应和缺陷的可逆性表明 CD1d 和 Fas 阳性 T 细胞恶性肿瘤中 iNKT 细胞的独特操纵。
