Peripheral tolerance can be modified by altering KLF2-regulated Treg migration
Peripheral tolerance can be modified by altering KLF2-regulated Treg migration
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DOI：
10.1073/pnas.1605849113
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发表时间：
2016-08-09
影响因子：
11.1
通讯作者：
Sebzda, Eric
中科院分区：
文献类型：
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作者：
Pabbisetty, Sudheer K.;Rabacal, Whitney;Sebzda, Eric
treg对于维持外周耐受性至关重要，因此靶向这些细胞可能分别通过增强或减少抑制功能来帮助治疗自身免疫和癌症。在这些细胞被用于治疗目的之前，有必要了解它们如何在生理相关条件下保持耐受性。我们现在报道转录因子kruppel样因子2 （KLF2）通过调节稳态和炎症归巢受体来控制初始Treg迁移模式，并且在缺乏KLF2的情况下，缺乏KLF2的Treg无法有效迁移到次级淋巴器官（slo）。Treg转运到slo的减少足以启动自身免疫，这表明slo是在稳态条件下维持外周耐受性的主要部位。疾病严重程度与受损的Treg向slo募集相关，相反，促进Treg进入这些组织可以改善自身免疫。此外，通过将这些抑制细胞从三级组织转移到slo，稳定Treg室内KLF2的表达可以增强外周耐受性。综上所述，这些结果表明外周耐受性通过调节Treg向slo的转运而增强或减弱，这一过程可以通过调节KLF2蛋白水平来控制。
Tregs are essential for maintaining peripheral tolerance, and thus targeting these cells may aid in the treatment of autoimmunity and cancer by enhancing or reducing suppressive functions, respectively. Before these cells can be harnessed for therapeutic purposes, it is necessary to understand how they maintain tolerance under physiologically relevant conditions. We now report that transcription factor Kruppel-like factor 2 (KLF2) controls naive Treg migration patterns via regulation of homeostatic and inflammatory homing receptors, and that in its absence KLF2-deficient Tregs are unable to migrate efficiently to secondary lymphoid organs (SLOs). Diminished Treg trafficking to SLOs is sufficient to initiate autoimmunity, indicating that SLOs are a primary site for maintaining peripheral tolerance under homeostatic conditions. Disease severity correlates with impaired Treg recruitment to SLOs and, conversely, promotion of Tregs into these tissues can ameliorate autoimmunity. Moreover, stabilizing KLF2 expression within the Treg compartment enhances peripheral tolerance by diverting these suppressive cells from tertiary tissues into SLOs. Taken together, these results demonstrate that peripheral tolerance is enhanced or diminished through modulation of Treg trafficking to SLOs, a process that can be controlled by adjusting KLF2 protein levels.