Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation

• Published in: Scientific reports Vol. 9; no. 1; pp. 13867 - 18
• Main Authors: Dhar, Atika, Chawla, Meenakshi, Chattopadhyay, Somdeb, Oswal, Neelam, Umar, Danish, Gupta, Suman, Bal, Vineeta, Rath, Satyajit, George, Anna, Arimbasseri, G. Aneeshkumar, Basak, Soumen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.09.2019; Nature Publishing Group
• Subjects: 13; 13/106; 13/31; 14; 38; 631/250/1619/554/1898/1271; 631/250/516/1909; 82; 82/29; Animals; CD4 antigen; Cell activation; Chimeras; Flow Cytometry; Genotypes; Homeostasis; Humanities and Social Sciences; Lymphocyte Activation; Lymphocytes T; Lymphoid tissue; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; NF-kappa B p52 Subunit - metabolism; NF-kappa B p52 Subunit - physiology; NF-κB protein; Organogenesis; Phenotypes; RelA protein; RelB protein; Science; Science (multidisciplinary); T-Lymphocytes, Regulatory - metabolism; Thymus; Transcriptome
• ISSN: 2045-2322; 2045-2322
• 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.