Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation
Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation
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DOI：
10.1038/s41598-019-50454-z
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发表时间：
2019-09-25
影响因子：
4.6
通讯作者：
Basak, Soumen
中科院分区：
文献类型：
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作者：
Dhar, Atika;Chawla, Meenakshi;Basak, Soumen
核因子-κ B（NF-κ B B）途径的免疫学作用是通过免疫应答中的经典组分和免疫器官发生和稳态中的非经典组分介导的，尽管这两种组分能够相互干扰。调节性CD 4 T细胞（TCF 4）具有稳态功能，代表了这两种NF-κ B组分的有趣的潜在交汇点。我们发现，非典型NF-κ B B组分基因Nfkb 2（p100）缺陷的小鼠具有正常的胸腺发育和抑制胸腺发育的功能。然而，他们的外周效应表型TbR（eTbR）的频率增加。在野生型（WT）和Nfkb 2-/-小鼠的双亲嵌合体中，Nfkb 2-/-基因型在Tcb中过度表达，eTcb的相对显著性进一步增加。与eTclad的不同性质一致，Nfkb 2-/-基因型在Tclad中在淋巴外组织中更突出，例如在双亲嵌合体中的肝脏。Nfkb 2-/-TcB在体内也表现出更大的存活、活化和增殖。这些Nfkb 2-/-TclB显示出较高的核NF-.B活性，主要由含有RelB的二聚体组成，与WT TclB中含有cRelA和RelA的二聚体的显著性相反。由于p100是RelB活化的抑制剂，也是RelB核活性中裂解的p52的参与者，我们测试了WT和Relb-/-小鼠的双亲嵌合体，并在这些嵌合体小鼠中发现了Relb-/-TbR和eTbR的正常频率。我们的研究结果证实并扩展了最近的数据，并表明p100通常抑制RelB介导的Treg激活，在没有p100的情况下，p50-RelB二聚体可以促进Treg激活。
The immunological roles of the nuclear factor-kappaB (NF-.B) 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-kappa B components. We show that mice deficient in the non-canonical NF-.B 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-.B 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 biparental 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.