Understanding the Roles of the NF-κB Pathway in Regulatory T Cell Development, Differentiation and Function

Fulford, Thomas S; Ellis, Darcy; Gerondakis, Steve

doi:10.1016/bs.pmbts.2015.08.002

Cited by 12 publications

(5 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Considering the observations that NF-κB transcription factors and especially c-Rel modulates various steps of T reg cell development including the generation of thymic T reg cell progenitors before Foxp3 expression ( 48 ), we examined thymic T reg precursors in the absence of A20. Mice with A20 −/− T cells exhibited increased frequencies of CD25 + Foxp3 − CD4SP thymocytes, revealing an enhanced T reg cell precursor compartment ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, A20 −/− thymic T reg cells showed reduced nuclear translocation of the NF-κB subunit c-Rel. Because NF-κB signaling was shown to modulate multiple steps of T reg cell development in the thymus ( 48 ), we hypothesize that A20 influences the thymic development of natural T reg cells through modulation of NF-κB activation in T reg cell progenitors. In line with this hypothesis, we discovered that the population increase in CD4 A20 −/− compared with CD4 A20 +/+ mice was not restricted to the Foxp3 + thymic T reg cell compartment, but was also comparably elevated in CD4SP CD25 + GITR + Foxp3 − thymic T reg cell progenitors.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A20 Restrains Thymic Regulatory T Cell Development

Fischer

Otten

Kober

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (Treg) cells in the thymus. Activation of NF-κB transcription factors is critically required for Treg cell development, partly via initiating Foxp3 expression. NF-κB activation is controlled by a negative feedback regulation through the ubiquitin editing enzyme A20, which reduces proinflammatory signaling in myeloid cells and B cells. In naive CD4+ T cells, A20 prevents kinase RIPK3-dependent necroptosis. Using mice deficient for A20 in T lineage cells, we show that thymic and peripheral Treg cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic Treg differentiation. A20-deficient thymic Treg cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-κB transcription factor RelA was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic Treg cells. Furthermore, we found that the increase in Treg cells in T cell–specific A20-deficient mice was already observed in CD4+ single-positive CD25+ GITR+ Foxp3− thymic Treg cell progenitors. Treg cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic Treg cell development. A20-deficient Treg cells efficiently suppressed effector T cell–mediated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, suggesting normal suppressive function. Holding thymic production of natural Treg cells in check, A20 thus integrates Treg cell activity and increased effector T cell survival into an efficient CD4+ T cell response.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A20 Restrains Thymic Regulatory T Cell Development

Fischer

Otten

Kober

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…As an important mediator of inflammation, c‐Rel plays a dual role in mature lymphocytes. On the one hand, it promotes pro‐inflammatory effector immune responses in Tcon 40 . On the other hand, it is required for the maintenance of Treg identity because aTregs lacking c‐Rel exhibit a complete loss of function 15 .…”

Section: Discussionmentioning

confidence: 99%

Targeting NF-κB c-Rel in regulatory T cells to treat corneal transplantation rejection

Bian

Wang

Sun

et al. 2021

American Journal of Transplantation

View full text Add to dashboard Cite

The relevance of Tregs in the induction of tolerance against corneal allografts has been well established. Although it is well known that the conversion of Tregs into effector‐like cells contributes to the loss of corneal immune privilege, the underlying mechanism is still not fully understood. Using heterologous penetrating keratoplasty model, we found that Tregs from corneal allograft rejected mice (inflam‐Tregs) exhibit impaired function and characteristics of effector T cells. Further study showed that the expression of NF‐κB c‐Rel, a key mediator of effector T cell function, was significantly increased in inflam‐Tregs. Mechanistic study revealed that elevated NF‐κB c‐Rel level in inflam‐Tregs impaired Treg function through the promotion of inflammatory cytokine production and glycolysis. More importantly, we demonstrated that targeting NF‐κB c‐Rel was able to improve the immune suppressive function of inflam‐Tregs in vitro and enhance the potential of them to suppress corneal transplantation rejection. Therefore, our current study identified NF‐κB c‐Rel as a key mediator of the conversion of Tregs into effector‐like cells when under inflammatory environment.

show abstract

“…NF-κB signaling pathway is one of the most important pathways that is activated under a pathogen challenge ( 17 , 18 ), and its modulation confers a therapeutic target in autoimmunity ( 19 ). The members of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) family in mammalian cells include the proto-oncogene c-Rel, p50/p105 (NF-κB1), p65 (Rel A), p52/p100 (NF-κB2), and Rel B ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Lapiferin protects against H1N1 virus-induced pulmonary inflammation by negatively regulating NF-kB signaling

Pei

Gao²,

et al. 2020

Braz J Med Biol Res

View full text Add to dashboard Cite

H1N1 virus-induced excessive inflammatory response contributes to severe disease and high mortality rates. There is currently no effective strategy against virus infection in lung. The present study evaluated the protective roles of a natural compound, lapiferin, in H1N1 virus-induced pulmonary inflammation in mice and in cultured human bronchial epithelial cells. Initially, Balb/C mice were grouped as Control, H1N1 infection (intranasally infected with 500 plaque-forming units of H1N1 virus), lapiferin (10 mg/kg), and H1N1+lapiferin (n=10/group). Lung histology, expression of inflammatory factors, and survival rates were assessed after 14 days of exposure. Administration of lapiferin significantly alleviated the virus-induced inflammatory infiltrate in lung tissues. Major pro-inflammatory cytokines, such as interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a, were decreased at both mRNA and protein levels by lapiferin administration in the lung homogenate. Lapiferin also reduced inflammatory cell numbers in bronchoalveolar fluid. Mechanistically, lapiferin suppressed the transcriptional activity and protein expression of NF-kB p65, causing inhibition on NF-kB signaling. Pre-incubation of human bronchial epithelial cells with an NF-kB signaling specific activator, ceruletide, significantly blunted lapiferin-mediated inhibition of pro-inflammatory cytokines secretion in an air-liquid-interface cell culture experiment. Activation of NF-kB signaling also blunted lapiferin-ameliorated inflammatory infiltrate in lungs. These results suggested that lapiferin was a potent natural compound that served as a therapeutic agent for virus infection in the lung.

show abstract

Understanding the Roles of the NF-κB Pathway in Regulatory T Cell Development, Differentiation and Function

Cited by 12 publications

References 38 publications

A20 Restrains Thymic Regulatory T Cell Development

A20 Restrains Thymic Regulatory T Cell Development

Targeting NF-κB c-Rel in regulatory T cells to treat corneal transplantation rejection

Lapiferin protects against H1N1 virus-induced pulmonary inflammation by negatively regulating NF-kB signaling

Contact Info

Product

Resources

About