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The Role of Natural Killer T Cells in B Cell Lymphoma.

机译：自然杀手T细胞在B细胞淋巴瘤中的作用。

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摘要

Natural killer T (NKT) cells are a unique subset of T cells that recognize glycolipid antigens in the context of CD1d, a non-classical MHC class I-like molecule. NKT cells mount strong anti-tumor responses and are a major focus in developing effective cancer immunotherapy. However, little is known about the regulation of CD1d-mediated antigen presentation to NKT cells, particularly in the context of B cell lymphoma. Pro-survival factors of the Bcl-2 family, such as Bcl-xL are often upregulated in B cell lymphomas, and are associated with changes in the endocytic pathway, which is paramount for CD1d-mediated antigen presentation. We hypothesized that Bcl-xL can regulate this process, and found that over-expression or induction of Bcl-xL led to increased CD1d-mediated antigen presentation to NKT cells. Conversely, pharmacological inhibition or shRNA-mediated knockdown of Bcl-xL led to decreased antigen presentation. Surface CD1d expression was unchanged by the modulation of Bcl-xL, but its knockdown resulted in reduced CD1d trafficking to LAMP1+ compartments. Furthermore, Rab7, a late endosomal marker was upregulated following Bcl-xL knockdown, and CD1d molecules accumulated in the late endosomes. These results demonstrate that Bcl-xL modulates CD1d-mediated antigen presentation to NKT cells by altering the intracellular trafficking of CD1d. Thus, we have identified a potential tumor recognition mechanism that can impact current therapies targeting the Bcl-2 family, as well as emerging NKT cell based cancer immunotherapeutic strategies. We further studied the role of NKT cells in mantle cell lymphoma, a particularly aggressive form of non-Hodgkin's lymphoma, in vivo, using an IL-14&agr; and c-Myc double-transgenic mouse model. We found that treatment with a single dose of the NKT cell agonist &agr;-Galactosylceramide, increased survival and caused amelioration of disease. Ex vivo restimulation of splenocytes with &agr;-GalCer showed increased IFN-gamma responses, providing some insight into the mechanism underlying the enhanced anti-tumor response following &agr;-GalCer administration. These studies indicate that NKT cells play an important role in mediating an effective immune response to lymphoma, warranting further investigation of the CD1d/NKT system. This small but powerful lymphocyte population bears high potential for translation into the next generation of cancer therapy.
机译：天然杀伤性T细胞（NKT）是T细胞的唯一子集，可在非经典的MHC I类分子CD1d中识别糖脂抗原。 NKT细胞具有强大的抗肿瘤反应，是开发有效的癌症免疫疗法的主要重点。但是，关于CD1d介导的抗原呈递给NKT细胞的调节知之甚少，特别是在B细胞淋巴瘤的情况下。 Bcl-2家族的生存前因子，例如Bcl-xL，通常在B细胞淋巴瘤中被上调，并且与内吞途径的改变有关，这对于CD1d介导的抗原呈递至关重要。我们假设Bcl-xL可以调节这一过程，并发现Bcl-xL的过表达或诱导导致CD1d介导的抗原呈递给NKT细胞的增加。相反，药理学抑制或shRNA介导的Bcl-xL的敲低导致抗原呈递减少。通过调节Bcl-xL，表面CD1d的表达没有改变，但是其敲低导致CD1d向LAMP1 +区室的运输减少。而且，Bcl-xL敲低后，晚期内体标记Rab7被上调，并且CD1d分子在晚期内体中积累。这些结果表明，Bcl-xL通过改变CD1d的细胞内运输来调节CD1d介导的抗原呈递给NKT细胞。因此，我们已经确定了一种潜在的肿瘤识别机制，该机制可能会影响针对Bcl-2家族的当前疗法以及新兴的基于NKT细胞的癌症免疫治疗策略。我们使用IL-14＆agr;在体内进一步研究了NKT细胞在套细胞淋巴瘤中的作用，套细胞淋巴瘤是一种非霍奇金淋巴瘤的特别具有侵略性的形式。和c-Myc双转基因小鼠模型。我们发现用单剂量的NKT细胞激动剂α-半乳糖苷神经酰胺治疗可以提高生存率并改善疾病。用-GalCer进行脾细胞的离体再刺激显示增加的IFN-γ反应，提供了对施用-GalCer后增强抗肿瘤反应的潜在机制的一些见解。这些研究表明，NKT细胞在介导对淋巴瘤的有效免疫应答中起着重要作用，有待进一步研究CD1d / NKT系统。这种小而强大的淋巴细胞群具有转化为下一代癌症治疗的巨大潜力。

著录项

  • 作者

    Balasubrahmanyam, Priyanka.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Cellular biology.;Oncology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 168 p.
  • 总页数 168
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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