1. Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation
- Author
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Atika Dhar, Meenakshi Chawla, Neelam Oswal, G. Aneeshkumar Arimbasseri, Anna George, Satyajit Rath, Danish Umar, Somdeb Chattopadhyay, Soumen Basak, Suman Gupta, and Vineeta Bal
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0301 basic medicine ,Regulatory T cell ,lcsh:Medicine ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Article ,Flow cytometry ,Transcriptome ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,NF-kappa B p52 Subunit ,In vivo ,medicine ,Animals ,Homeostasis ,NF-kappaB ,lcsh:Science ,Mice, Knockout ,Multidisciplinary ,medicine.diagnostic_test ,Chemistry ,RELB ,lcsh:R ,Regulatory T cells ,Flow Cytometry ,Cell biology ,Mice, Inbred C57BL ,Crosstalk (biology) ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Q ,030215 immunology - Abstract
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.
- Published
- 2019
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