Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India.
Eur J Immunol. 2014 Feb;44(2):431-9. doi: 10.1002/eji.201343649. Epub 2013 Dec 4.
Leprosy is a chronic infectious disease caused by Mycobacterium leprae. FoxP3 have been shown to have important implications in various diseases. The present study describes the mechanism of action of FoxP3 in CD4⁺CD25⁺ T cells derived from leprosy patients. Increased molecular interactions of FoxP3 with histone deacetylases 7/9 in the nucleus of CD4⁺CD25⁺ T cells derived from borderline lepromatous leprosy/lepromatous leprosy (BL/LL) patients were found to be responsible for FoxP3-driven immune suppression activities during the progression of leprosy. Further, downregulation of CTLA-4 and CD25 genes in siFoxP3-treated PBMCs derived from BL/LL patients elucidated the transcription-activating nature of FoxP3. This observation was supported by direct binding of FoxP3 to the promoter region of the CTLA-4 and CD25 genes, and FoxP3's molecular interaction with histone acetyl transferases. The study also revealed that the increased expression of miR155 in CD4⁺CD25⁺ cells from BL/LL governs the competitive fitness of these cells. Again, reduced Annexin V & propidium iodide staining and Nur77 expression, and concomitantly increased Ki-67 positivity suggested that CD4⁺CD25⁺ cells derived from BL/LL patients are more competitively fit than those from borderline tuberculoid leprosy/tuberculoid leprosy and healthy controls. Taken together, the study shows the orchestration of FoxP3 leading to competitive fitness of Treg cells in leprosy.
麻风病是由麻风分枝杆菌引起的慢性传染病。FoxP3 在各种疾病中具有重要意义。本研究描述了 FoxP3 在麻风病患者来源的 CD4⁺CD25⁺T 细胞中的作用机制。研究发现，来自边界性瘤型麻风/瘤型麻风（BL/LL）患者的 CD4⁺CD25⁺T 细胞核中 FoxP3 与组蛋白去乙酰化酶 7/9 的分子相互作用增加，导致 FoxP3 驱动的免疫抑制活性在麻风病进展过程中增强。此外，在来自 BL/LL 患者的 PBMCs 中用 siFoxP3 处理后下调 CTLA-4 和 CD25 基因，阐明了 FoxP3 的转录激活特性。FoxP3 与 CTLA-4 和 CD25 基因启动子区域的直接结合以及 FoxP3 与组蛋白乙酰转移酶的分子相互作用支持了这一观察结果。该研究还表明，BL/LL 患者来源的 CD4⁺CD25⁺细胞中 miR155 的表达增加，调控这些细胞的竞争适应性。同样，减少 Annexin V 和碘化丙啶染色以及 Nur77 表达，同时增加 Ki-67 阳性率表明，BL/LL 患者来源的 CD4⁺CD25⁺细胞比边界性结核样型麻风/结核样型麻风患者和健康对照者具有更强的竞争适应性。总之，该研究表明 FoxP3 的协调作用导致麻风病中 Treg 细胞的竞争适应性。
