Survival and maintenance of regulatory T cells require the kinase TAK1

Chang, Jae Hoon; Hu, Hongbo; Sun, Shao Cong

doi:10.1038/cmi.2015.27

Cited by 20 publications

(11 citation statements)

References 37 publications

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“…35, 37–41 However, we did not find evidence of apoptosis. Instead and more importantly, using genetic fate tracing, and immunostaining for Akr1b7 and in situ hybridization for miR-330-5p, we found that the renin null cells did not disappear.…”

Section: Discussioncontrasting

confidence: 76%

Chronic Stimulation of Renin Cells Leads to Vascular Pathology

et al. 2017

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Experimental or spontaneous genomic mutations of the renin-angiotensin system or its pharmacological inhibition in early life leads to renal abnormalities including poorly developed renal medulla, papillary atrophy, hydronephrosis, inability to concentrate the urine, polyuria, polydipsia, renal failure and anemia. At the core of such complex phenotype is the presence of unique vascular abnormalities: the renal arterioles do not branch or elongate properly and they have disorganized, concentric hypertrophy. This lesion has been puzzling because it is often found in hypertensive individuals whereas mutant or pharmacologically inhibited animals are hypotensive. Remarkably, when renin cells are ablated with diphtheria toxin, the vascular hypertrophy does not occur suggesting that renin cells per se may contribute to the vascular disease. To test this hypothesis, on a Ren1c−/− background, we generated mutant mice with reporter expression (Ren1c−/−;Ren1c-Cre;R26R.mTmG; and Ren1c−/−;Ren1c-Cre;R26R.LacZ ) to trace the fate of reninnull cells. To assess whether reninnull cells maintain their renin promoter active, we used Ren1c−/−;Ren1c-YFP mice which transcribe YFP directed by the renin promoter. We also followed the expression of Akr1b7 and miR-330-5p, markers of cells programmed for the renin phenotype. Contrary to what we expected, reninnull cells did not die or disappear. Instead, they survived, increased in number along the renal arterial tree, and maintained an active molecular memory of the myo-epitheliod renin phenotype. Further, null cells of the renin lineage occupied the walls of the arteries and arterioles in a chaotic, directionless pattern directly contributing to the concentric arterial hypertrophy.

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Section: Discussioncontrasting

confidence: 76%

Chronic Stimulation of Renin Cells Leads to Vascular Pathology

et al. 2017

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“…In contrast to the principal role in immune activation, recent studies using cell type-specific and conditional deletion approaches revealed anti-inflammatory functions of certain NF-kB components: IKKb deletion in non-immune cells such as keratinocytes promoted inflammation (Pasparakis, 2009) and stimulated IL-1b production in myeloid cells (Greten et al, 2007). Deletion of TGF-b-activated kinase 1 (TAK1), which is upstream of IKKb, reduced Treg numbers in mice and caused mild autoimmunity (Chang et al, 2015). Also dendritic cells (DCs) require NF-kB, both to induce immunity and to maintain immune tolerance (Baratin et al, 2015;Dissanayake et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells

et al. 2017

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Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-κB signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress. Mice lacking IKKβ in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3 Tregs. Also, pharmacological IKKβ inhibition reduced Treg numbers in the circulation by ∼50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKKβ inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKKβ inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKKβ inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKKβ represents a druggable checkpoint.

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“…In different cell types, activation of TAK1 can be triggered by diverse stimuli, including TGF-b, TNF-a, IL-1, and Toll-like receptors, 29 resulting in a broad spectrum of actions, including embryogenesis, 33 generation of CD4 1 and CD8 1 thymocytes, and development of CD4 1 CD25 1 regulatory T cells. [34][35][36] The results of kinetic experiments showed robust Tak1 gene expression at early time points, as early as 6 hours after addition of TGF-b, suggesting that TAK1 might be relevant during the initial stages of differentiation. Expression of Tak1, similar to expression of Foxp3, was TGF-b dose dependent but not dependent on IL-6.…”

Section: Discussionmentioning

confidence: 99%