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.
Highlights
Regulatory T cells expressing the characteristic lineage determining transcription factor FOXP3 are actively involved in suppressing overt activation of the immune system and the development of autoimmunity[1]
Most Tregs in secondary lymphoid organs express high levels of CD62L12 and CCR713 like naive conventional T cells, and are termed central Tregs[14]. These cTregs are activated in the periphery[11] and give rise to effector Tregs showing surface phenotypes similar to recently activated conventional T cells, such as lower levels of CCR7 and CD62L14
The effector Tregs (eTregs) are more prominent in non-lymphoid tissues[13], short lived[11], express lower levels of Bcl-214 and contain a greater proportion of homeostatically proliferating cells compared to cTregs[11]
Summary
Regulatory T cells expressing the characteristic lineage determining transcription factor FOXP3 are actively involved in suppressing overt activation of the immune system and the development of autoimmunity[1]. The peripheral Treg population includes thymic-origin Tregs (‘natural’ Tregs (nTregs)) and Tregs that have been induced in the periphery from conventional CD4 T cells (‘induced’ Tregs (iTregs))[6] Tregs perform their functions through a number of mechanisms such as by competing for IL-2 with activated conventional T cells[7], by secreting cytokines such as IL-10 which regulates T cell activation and cytokine production[8], through direct killing mediated by perforin or granzyme production[9], and by interfering with T cell-dendritic cell interactions[10]. Most Tregs in secondary lymphoid organs express high levels of CD62L12 and CCR713 like naive conventional T cells, and are termed central Tregs (cTregs)[14]. The absence of TCR signals leads to loss of expression of target genes of NFAT indicating its possible role in eTreg generation and maintenance[19,20]. In addition to IRF4 and BLIMP1, the transcription factors of the canonical NF-κB family have been shown to play a role in eTreg generation and/or maintenance. Hetero-dimers of p52 and RelB constitute the activity of the non-canonical NF-κB pathway, which is activated through a select set of TNFR superfamily members like CD40, OX-40, GITR and LT-βR26,27
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