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首页> 外文OA文献 >The Role of T cell-associated Polarizing Transcription Factors in Dendritic cell Priming of T cells towards Immunity or Tolerance; role of T-bet or Foxp3 ectopic expression in Dendritic cells
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The Role of T cell-associated Polarizing Transcription Factors in Dendritic cell Priming of T cells towards Immunity or Tolerance; role of T-bet or Foxp3 ectopic expression in Dendritic cells

机译：T细胞相关极化转录因子在T细胞对免疫或耐受的树突状细胞启动中的作用； T-bet或Foxp3异位表达在树突状细胞中的作用

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摘要

Dendritic cells (DC) are professional antigen presenting cells that can prime naïve T cells to elicit immunity or tolerance. The ability to regulate immunity or tolerance is governed by the "type" of polarization state of these activated T cells. T-bet (T-box expressed in T cells) has been identified as the master regulator of Type 1 polarization in T cells, and its expression in T cells is essential for immunity. Conversely, Foxp3 expression in T cells (T regulatory cells) engenders a tolerogenic phenotype that can suppress immunity in Type-1, as well as the Type-2 and -17 subsets, and DC. Interestingly, T-bet is also expressed in DC and its abolishment resulted in impaired Type-1 T cell responses. Furthermore, Foxp3 expression in non-T cell subsets, such as adenocarinoma, has shown potent immunosuppressive characteristics in the tumor microenvironment and draining lymph nodes. Therefore, we examined the role of adenoviral transduced T-bet and Foxp3 in the myeloid cell lineage, specifically monocyte-derived DC. We evaluated the phenotypic expression of DC and T cell responses upon priming by T-bet expressing DC (DC.bet) or Foxp3 expressing DC (DC.Fox). DC.bet potently primed naïve T cells towards Type 1 immunity, inducing 2-3 fold increased levels of T-bet, IFNγ, CXCR3, and Granzyme-B. Interestingly, we found little-to-no changes in costimulatory molecule expression. However, DC were completely impaired in production of Type-1-inducing cytokines. We confirmed cytokine-independent Type 1 polarization by using neutralization antibodies. More surprisingly, we found that Foxp3 in DC induced tolerance. Mechanisms included direct suppression of CD8+ T cell subsets and indirect suppression of Type-1 responses by increased generation of T regulatory cell subsets. These generated DC.Fox induced-Tregs (XiTregs) expressed high levels of CTLA-4, CD25, and GITR and concomitantly suppressed naïve and memory CD8+ T cell proliferation and IFNγ production. Neutralizing agents confirmed that tryptophan catabolizing enzyme-IDO and TGFβ were important in suppressing generation of Tregs and effector functions of T cells. In summation, this work shows that T-bet and Foxp3 expression in DC play similar roles to expression in T cells by governing immunity or tolerance. Furthermore, this provides a basis for the usage of these DC in immunotherapies.
机译：树突状细胞（DC）是专业的抗原呈递细胞，可引发幼稚T细胞引发免疫或耐受。调节免疫或耐受性的能力由这些活化的T细胞的极化状态的“类型”决定。 T-bet（在T细胞中表达的T-box）已被确定为T细胞中1型极化的主要调节因子，其在T细胞中的表达对于免疫至关重要。相反，T细胞（T调节细胞）中的Foxp3表达产生了一种耐受性表型，可以抑制Type-1，Type-2和-17亚型以及DC的免疫力。有趣的是，T-bet也在DC中表达，其取消导致1型T细胞反应受损。此外，Foxp3在非T细胞亚群（如腺癌）中的表达在肿瘤微环境和引流淋巴结中显示出强大的免疫抑制特性。因此，我们检查了腺病毒转导的T-bet和Foxp3在髓样细胞谱系，特别是单核细胞衍生的DC中的作用。我们评估了表达T-bet的DC（DC.bet）或表达Foxp3的DC（DC.Fox）引发的DC和T细胞反应的表型表达。 DC.bet可以有效地激发纯正T细胞达到1型免疫力，诱导T-bet，IFNγ，CXCR3和Granzyme-B水平提高2-3倍。有趣的是，我们发现共刺激分子表达几乎没有变化。但是，DC在诱导1型细胞因子的生产中完全受损。我们通过使用中和抗体证实了细胞因子非依赖性的1型极化。更令人惊讶的是，我们发现Foxp3在DC诱导耐受。机制包括直接抑制CD8 + T细胞亚群和通过增加T调节细胞亚群的产生间接抑制Type-1反应。这些产生的DC.Fox诱导Treg（XiTreg）表达高水平的CTLA-4，CD25和GITR，并同时抑制幼稚和记忆CD8 + T细胞的增殖以及IFNγ的产生。中和剂证实，色氨酸分解酶IDO和TGFβ在抑制Treg的产生和T细胞的效应子功能中很重要。总而言之，这项工作表明DC中的T-bet和Foxp3表达通过控制免疫力或耐受性而发挥与T细胞中表达相似的作用。此外，这为在免疫疗法中使用这些DC提供了基础。

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    Lipscomb Michael Wheeler;

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  • 年度 2009
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