c‐Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice

Fulford, Thomas S; Grumont, Raelene J.; Wirasinha, Rushika C.; Ellis, Darcy; Barugahare, Adele; Turner, Stephen J.; Naeem, Haroon; Powell, David R.; Lyons, Paul; Smith, Kenneth G. C.; Scheer, Sebastian; Zaph, Colby; Klein, Ulf; Daley, Stephen R.; Gerondakis, Steve

doi:10.1002/eji.202048900

Cited by 8 publications

(6 citation statements)

References 109 publications

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“…In contrast to animals with systemic c-Rel deficiency, mice with conditional deletion of c-Rel in Treg cells develop signs of inflammation with age, and c-Rel-deficient Treg cells are unable to control pathogenic T cells in a T cell transfer colitis model [ 26 ], demonstrating a role for c-Rel in Treg cell–mediated immune control. This was also observed in cell transfer experiments which showed that c-Rel knockout Treg cells are deficient in controlling the expansion of wild-type T cells in lymphopenic hosts [ 22 ]. Along the same line, conditional ablation of c-Rel in Treg cells affects a distinct set of genes (around 300 are up- and 350 downregulated) [ 26 ].…”

Section: Canonical Nf-κb Transcription Factors and Treg Cell Functionmentioning

confidence: 71%

“…C-Rel employs multiple mechanisms to promote the differentiation as well as thymic and peripheral functions of Treg cells in mice [ 10 , 22 , 23 ]. Indeed, c-Rel can currently be considered as the NF-κB members with the most profound effects on Treg cell biology (see Fig.…”

Section: Canonical Nf-κb Transcription Factors and Treg Cell Functionmentioning

confidence: 99%

“…Interestingly, c-Rel-deficient mice do not develop lymphoproliferative or autoimmune disease even though they have only 15% of normal Treg cell numbers, most likely due to general immune deficiency [ 23 , 26 ]. The deficit in c-Rel-deficient Treg cells manifests already in thymic Treg differentiation and is primarily of quantitative and not qualitative nature [ 22 ]. Thus, c-Rel may serve as a switch for developing Treg cells, and it will be interesting to study whether the few developing c-Rel-deficient Treg cells have a skewed TCR repertoire with a distinct affinity for MHC:peptide complexes.…”

Section: Canonical Nf-κb Transcription Factors and Treg Cell Functionmentioning

confidence: 99%

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NF-κB in control of regulatory T cell development, identity, and function

2022

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Regulatory T cells (Treg cells) act as a major rheostat regulating the strength of immune responses, enabling tolerance of harmless foreign antigens, and preventing the development of pathogenic immune responses in various disease settings such as cancer and autoimmunity. Treg cells are present in all lymphoid and non-lymphoid tissues, and the latter often fulfill important tasks required for the physiology of their host organ. The activation of NF-κB transcription factors is a central pathway for the reprogramming of gene expression in response to inflammatory but also homeostatic cues. Genetic mouse models have revealed essential functions for NF-κB transcription factors in modulating Treg development and function, with some of these mechanistic insights confirmed by recent studies analyzing Treg cells from patients harboring point mutations in the genes encoding NF-κB proteins. Molecular insights into the NF-κB pathway in Treg cells hold substantial promise for novel therapeutic strategies to manipulate dysfunctional or inadequate cell numbers of immunosuppressive Treg cells in autoimmunity or cancer. Here, we provide an overview of the manifold roles that NF-κB factors exert in Treg cells.

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Section: Canonical Nf-κb Transcription Factors and Treg Cell Functionmentioning

confidence: 71%

Section: Canonical Nf-κb Transcription Factors and Treg Cell Functionmentioning

confidence: 99%

Section: Canonical Nf-κb Transcription Factors and Treg Cell Functionmentioning

confidence: 99%

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NF-κB in control of regulatory T cell development, identity, and function

2022

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“…To find out the functional significance of transcription factor c-Rel downregulation in SM + M, M, and SM Tregs, we reasoned that if c-Rel is critical in promoting Treg generation and suppressive function, Rel deficiency in Tregs will lead to downregulation of significant numbers of genes in Tregs. Through our search in NIH-NCBI GeoDatasets database, we found that an Australian group published a paper on RNA Seq datasets from c-Rel deficiency (KO) in Tregs (GSE154166) [ 105 ]. We found that 35 genes were shared by the downregulated gene list from SM + M Tregs and the downregulated gene list from c-Rel knockout (KO) Tregs ( Figure 7 K).…”

Section: Resultsmentioning

confidence: 99%

Cigarette Smoke and Morphine Promote Treg Plasticity to Th17 via Enhancing Trained Immunity

Shao

Saaoud

Cornwell

et al. 2022

Cells

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CD4+ regulatory T cells (Tregs) respond to environmental cues to permit or suppress inflammation, and atherosclerosis weakens Treg suppression and promotes plasticity. However, the effects of smoking plus morphine (SM + M) on Treg plasticity remain unknown. To determine whether SM + M promotes Treg plasticity to T helper 17 (Th17) cells, we analyzed the RNA sequencing data from SM, M, and SM + M treated Tregs and performed knowledge-based and IPA analysis. We demonstrated that (1) SM + M, M, and SM upregulated the transcripts of cytokines, chemokines, and clusters of differentiation (CDs) and modulated the transcripts of kinases and phosphatases in Tregs; (2) SM + M, M, and SM upregulated the transcripts of immunometabolism genes, trained immunity genes, and histone modification enzymes; (3) SM + M increased the transcripts of Th17 transcription factor (TF) RORC and Tfh factor CXCR5 in Tregs; M increased the transcripts of T helper cell 1 (Th1) TF RUNX3 and Th1-Th9 receptor CXCR3; and SM inhibited Treg TGIF1 transcript; (4) six genes upregulated in SM + M Tregs were matched with the top-ranked Th17 pathogenic genes; and 57, 39 genes upregulated in SM + M Tregs were matched with groups II and group III Th17 pathogenic genes, respectively; (5) SM + M upregulated the transcripts of 70 IPA-TFs, 11 iTregs-specific TFs, and 4 iTregs-Th17 shared TFs; and (6) SM + M, M, and SM downregulated Treg suppression TF Rel (c-Rel); and 35 SM + M downregulated genes were overlapped with Rel-/- Treg downregulated genes. These results provide novel insights on the roles of SM + M in reprogramming Treg transcriptomes and Treg plasticity to Th17 cells and novel targets for future therapeutic interventions involving immunosuppression in atherosclerotic cardiovascular diseases, autoimmune diseases, transplantation, and cancers.

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“…After CD4SP thymocytes initiate strong TCR signaling in the medulla, the thymocyte-intrinsic pathways required to prevent deletion change as the thymocyte matures. Canonical NF-κB activation prevents deletion within the Foxp3 – T-reg precursor stage ( 22 , 87 – 89 ), whereas IL-2 signaling prevents deletion at a later stage, close to the time of Foxp3 upregulation ( 75 ). DOCK8 inhibits deletion at both of these stages ( 90 ).…”

Section: Impact Of Thymocyte Deletion In the Medulla On T-reg Selectionmentioning

confidence: 99%

How Thymocyte Deletion in the Cortex May Curtail Antigen-Specific T-Regulatory Cell Development in the Medulla

Wang

Daley

2022

Front. Immunol.

Self Cite

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CD4+ T cell responses to self-antigens are pivotal for immunological self-tolerance. Activation of Foxp3– T-conventional (T-conv) cells can precipitate autoimmune disease, whereas activation of Foxp3+ T-regulatory (T-reg) cells is essential to prevent autoimmune disease. This distinction indicates the importance of the thymus in controlling the differentiation of self-reactive CD4+ T cells. Thymocytes and thymic antigen-presenting cells (APC) depend on each other for normal maturation and differentiation. In this Hypothesis and Theory article, we propose this mutual dependence dictates which self-antigens induce T-reg cell development in the thymic medulla. We postulate self-reactive CD4+ CD8– thymocytes deliver signals that stabilize and amplify the presentation of their cognate self-antigen by APC in the thymic medulla, thereby seeding a niche for the development of T-reg cells specific for the same self-antigen. By limiting the number of antigen-specific CD4+ thymocytes in the medulla, thymocyte deletion in the cortex may impede the formation of medullary T-reg niches containing certain self-antigens. Susceptibility to autoimmune disease may arise from cortical deletion creating a “hole” in the self-antigen repertoire recognized by T-reg cells.

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c‐Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice

Cited by 8 publications

References 109 publications

NF-κB in control of regulatory T cell development, identity, and function

NF-κB in control of regulatory T cell development, identity, and function

Cigarette Smoke and Morphine Promote Treg Plasticity to Th17 via Enhancing Trained Immunity

How Thymocyte Deletion in the Cortex May Curtail Antigen-Specific T-Regulatory Cell Development in the Medulla

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