National Institute of Immunology, New Delhi, India.
Sci Rep. 2019 Sep 25;9(1):13867. doi: 10.1038/s41598-019-50454-z.
The immunological roles of the nuclear factor-kappaB (NF-κB) pathway are mediated via the canonical components in immune responses and via non-canonical components in immune organogenesis and homeostasis, although the two components are capable of crosstalk. Regulatory CD4 T cells (Tregs) are homeostatically functional and represent an interesting potential meeting point of these two NF-κB components. We show that mice deficient in the non-canonical NF-κB component gene Nfkb2 (p100) had normal thymic development and suppressive function of Tregs. However, they had enhanced frequencies of peripheral 'effector-phenotype' Tregs (eTregs). In bi-parental chimeras of wild-type (WT) and Nfkb2-/- mice, the Nfkb2-/- genotype was over-represented in Tregs, with a further increase in the relative prominence of eTregs. Consistent with distinct properties of eTregs, the Nfkb2-/- genotype was more prominent in Tregs in extra-lymphoid tissues such as liver in the bi-parental chimeras. The Nfkb2-/- Tregs also displayed greater survival, activation and proliferation in vivo. These Nfkb2-/- Tregs showed higher nuclear NF-κB activity mainly comprising of RelB-containing dimers, in contrast to the prominence of cRel- and RelA-containing dimers in WT Tregs. Since p100 is an inhibitor of RelB activation as well as a participant as cleaved p52 in RelB nuclear activity, we tested bi-parental chimeras of WT and Relb-/- mice, and found normal frequencies of Relb-/- Tregs and eTregs in these chimeric mice. Our findings confirm and extend recent data, and indicate that p100 normally restrains RelB-mediated Treg activation, and in the absence of p100, p50-RelB dimers can contribute to Treg activation.
核因子-κB（NF-κB）通路的免疫学作用是通过免疫反应中的经典成分和免疫器官发生和稳态中的非经典成分介导的，尽管这两个成分能够相互作用。调节性 CD4 T 细胞（Tregs）具有稳态功能，是这两个 NF-κB 成分的一个有趣的潜在交汇点。我们发现，非经典 NF-κB 成分基因 Nfkb2（p100）缺失的小鼠具有正常的胸腺发育和 Tregs 的抑制功能。然而，它们外周的“效应表型”Tregs（eTregs）频率增加。在野生型（WT）和 Nfkb2-/-小鼠的双亲嵌合体中，Nfkb2-/-基因型在 Tregs 中过度表达，eTregs 的相对突出程度进一步增加。与 eTregs 的不同特性一致，在双亲嵌合体中的肝等淋巴外组织中，Nfkb2-/-基因型在 Tregs 中更为突出。Nfkb2-/-Tregs 在体内也表现出更高的存活率、激活和增殖。这些 Nfkb2-/-Tregs 显示出更高的核 NF-κB 活性，主要由包含 RelB 的二聚体组成，而 WT Tregs 中则以包含 cRel 和 RelA 的二聚体为主导。由于 p100 既是 RelB 激活的抑制剂，也是包含 cleaved p52 的 RelB 核活性的参与者，因此我们测试了 WT 和 Relb-/-小鼠的双亲嵌合体，并在这些嵌合小鼠中发现了正常频率的 Relb-/-Tregs 和 eTregs。我们的研究结果证实并扩展了最近的数据，表明 p100 通常抑制 RelB 介导的 Treg 激活，在缺乏 p100 的情况下，p50-RelB 二聚体可以促进 Treg 激活。
