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首页> 外文期刊>Clinical and Translational Medicine >Interleukin‐2‐inducible T‐cell kinase (Itk) signaling regulates potent noncanonical regulatory T cells
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Interleukin‐2‐inducible T‐cell kinase (Itk) signaling regulates potent noncanonical regulatory T cells

机译：白细胞介素-2-诱导型T细胞激酶（ITK）信号传导调节有效的非甘露吞噬调节性T细胞

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Regulatory T cells (Tregs) play an important role in controlling autoimmunity and limiting tissue damage and inflammation. IL2‐inducible T cell kinase (Itk) is part of the Tec family of tyrosine kinases and is a critical component of T cell receptor mediated signaling. Here, we showed that either genetic ablation of Itk signaling or inhibition of Itk signaling pathways resulted in increased frequency of “noncanonical” CD4 ~(+)CD25 ~(?)FOXP3 ~(+) Tregs (ncTregs), as well as of “canonical” CD4 ~(+)CD25 ~(+)FOXP3 ~(+) Tregs (canTregs). Using in vivo models, we showed that ncTregs can avert the formation of acute graft‐versus‐host disease (GVHD), in part by reducing conventional T cell proliferation, proinflammatory cytokine production, and tissue damage. This reduction in GVHD occurred without disruption of graft‐versus‐leukaemia (GVL) effects. RNA sequencing revealed that a number of effector, cell adhesion, and migration molecules were upregulated in Itk ~(–/?) ncTregs. Furthermore, disrupting the SLP76: ITK interaction using a specific peptide inhibitor led to enhanced Treg development in both mouse and primary human cells. This peptide inhibitor also significantly reduced inflammatory cytokine production in primary GVHD patient samples and mouse T cells without causing cell death or apoptosis. We provide evidence that specifically targeting Itk signaling could be a therapeutic strategy to treat autoimmune disorders. Targeting Itk signaling resulted in increased CD25 ~(+) FOXP3 ~(+) canonical and CD25 ~(?), FoxP3 ~(+) noncanonical Tregs. Noncanonical Tregs inhibited GVHD induced by conventional CD8 ~(+) T cells, and reduced production of inflammatory cytokines in mice, without disrupting GVL effects. Disrupting ITK signaling using a specific peptide inhibitor reduced proinflammatory cytokine production by T cells in GVHD patient samples.
机译：调节性T细胞（Tregs）在控制自身免疫和限制组织损伤和炎症方面发挥着重要作用。 IL2-诱导型T细胞激酶（ITK）是Tyrosine激酶的TEC系列的一部分，是T细胞受体介导的信号传导的关键组分。在此，我们表明ITK信号传导或ITK信号传导途径的遗传消融导致“非甘露吞噬”CD4〜（+）CD25〜（？）Foxp3〜（+）Tregs（Nctregs）的频率增加，以及“规范“CD4〜（+）CD25〜（+）Foxp3〜（+）Tregs（Cantregs）。在体内模型中，我们表明，NCTREGS可以通过减少常规T细胞增殖，促炎细胞因子生产和组织损伤，NCTREGS可以避免急性移植物与宿主疾病（GVHD）的形成。这种降低的GVHD发生而不会破坏移植物与白血病（GVL）效应。 RNA测序显示，在ITK〜（ - / +）Nctregs中升高了许多效应，细胞粘附和迁移分子。此外，破坏SLP76：使用特定肽抑制剂的ITK相互作用导致小鼠和初级人细胞中的Treg发育增强。该肽抑制剂在初级GVHD患者样品和小鼠T细胞中也显着降低了炎症细胞因子产生，而不会引起细胞死亡或细胞凋亡。我们提供了专门针对ITK信号传导的证据可以是治疗自身免疫障碍的治疗策略。针对ITK信号传导导致CD25〜（+）Foxp3〜（+）规范和CD25〜（？），Foxp3〜（+）非甘露透止的Tregs。非甘露透明的Tregs抑制由常规CD8〜（+）T细胞诱导的GVHD，并降低小鼠中炎性细胞因子的产生，而不会破坏GVL效应。使用特定的肽抑制剂破坏ITK信号传导，通过GVHD患者样品中的T细胞降低促炎细胞因子产生。

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