Division of Life Science, College of Life Science and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
J Biol Chem. 2019 Nov 22;294(47):17951-17961. doi: 10.1074/jbc.RA119.010545. Epub 2019 Oct 9.
Naïve CD4 T cells in the periphery differentiate into regulatory T cells (Tregs) in which Foxp3 is expressed for their suppressive function. NLRP3, a pro-inflammatory molecule, is known to be involved in inflammasome activation associated with several diseases. Recently, the expression of NLRP3 in CD4 T cells, as well as in myeloid cells, has been described; however, a role of T cell-intrinsic NLRP3 in Treg differentiation remains unknown. Here, we report that NLRP3 impeded the expression of Foxp3 independent of inflammasome activation in Tregs. NLRP3-deficient mice elevate Treg generation in various organs in the pathway. NLRP3 deficiency increased the amount and suppressive activity of Treg populations, whereas NLRP3 overexpression reduced Foxp3 expression and Treg abundance. Importantly, NLRP3 interacted with Kpna2 and translocated to the nucleus from the cytoplasm under Treg-polarizing conditions. Taken together, our results identify a novel role for NLRP3 as a new negative regulator of Treg differentiation, mediated via its interaction with Kpna2 for nuclear translocation.
外周血中的幼稚 CD4 T 细胞在外周分化为调节性 T 细胞（Tregs），其表达 Foxp3 以发挥抑制功能。NLRP3 是一种促炎分子，已知其参与与多种疾病相关的炎症小体激活。最近，已经描述了 NLRP3 在 CD4 T 细胞以及髓样细胞中的表达；然而，T 细胞内源性 NLRP3 在 Treg 分化中的作用尚不清楚。在这里，我们报告 NLRP3 独立于炎症小体激活抑制 Treg 中 Foxp3 的表达。NLRP3 缺陷型小鼠在各种器官中增加 Treg 的生成。NLRP3 缺乏增加了 Treg 群体的数量和抑制活性，而 NLRP3 过表达降低了 Foxp3 的表达和 Treg 的丰度。重要的是，NLRP3 与 Kpna2 相互作用，并在 Treg 极化条件下从细胞质转位到细胞核。总之，我们的结果确定了 NLRP3 的一个新的作用，作为 Treg 分化的新的负调节剂，通过与 Kpna2 的相互作用介导核转位。
