RelB regulates Th17 differentiation in a cell-intrinsic manner

Koliesnik, Ievgen; Andreas, Nico; Romanov, Victor; Sreekantapuram, Sravya; Krljanac, Branislav; Haenold, Ronny; Weih, Falk

doi:10.1016/j.imbio.2017.10.026

Cited by 8 publications

(8 citation statements)

References 35 publications

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“…Similarly, RelB-deficient mice presented with damaged T cell immunity, a reduction of interferon-γ (IFN-γ) and multiorgan inflammation [53,62]. Emerging evidence reveals that RelB plays a negative role in Th17 differentiation [63]. Kurosawa et al observed that effector memory cells from RelB-deficient mice displayed significantly elevated migratory activity than that in the WT mice [64].…”

Section: T Cell Differentiation and T Cell-mediated Immunitymentioning

confidence: 99%

“…There is growing evidence that RelB is a negative factor regarding mediating Th17 cell differentiation and function, which affects the induction and progression of EAE [63,130,131]. Park et al showed that lipopolysaccharides directly stimulated Th17 cell differentiation, enhanced the frequency of IL-17producing cells and aggravated EAE via modulating phosphorylation of RelB and NF-κB1 [132].…”

Section: Th17 Cellsmentioning

confidence: 99%

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Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis

et al. 2019

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Transcription factor RelB is a member of the nuclear factror-kappa B (NF-κB) family, which plays a crucial role in mediating immune responses. Plenty of studies have demonstrated that RelB actively contributes to lymphoid organ development, dendritic cells maturation and function and T cells differentiation, as well as B cell development and survival. RelB deficiency may cause a variety of immunological disorders in both mice and humans. Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system which involves a board of immune cell populations. Thereby, RelB may exert an impact on MS by modulating the functions of dendritic cells and the differentiation of T cells and B cells. Despite intensive research, the role of RelB in MS and its animal model, experimental autoimmune encephalomyelitis, is still unclear. Herein, we give an overview of the biological characters of RelB, summarize the updated knowledge regarding the role of RelB in different cell types that contribute to MS pathogenesis and discuss the potential RelB-targeted therapeutic implications for MS.

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Section: T Cell Differentiation and T Cell-mediated Immunitymentioning

confidence: 99%

Section: Th17 Cellsmentioning

confidence: 99%

Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis

et al. 2019

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“…Flow cytometry was performed as previously described (31). Antibodies used included anti-CD4-BV785 (RM4-5), anti-CD8-BV711 (53-6.7), anti-CD62L-BV421 (MEl-14), anti-CD44-APC-Cy7 (IM7), anti-CD25-PE-Cy7-(PC61), anti-CD3-PE-Cy7 (17A2), anti-CD69-APC (H1.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Th1 and Th17 cells were induced as previously described (31). In brief, 1 × 10 5 naïve CD4 cells were activated with anti-CD3 (145-2C11, Biolegend) and anti-CD28 (37.51, Biolegend) antibodies in presence of 50 ng/ml mouse recombinant IL-12 or 5 ng/ml of human recombinant TGFβ (Biolegend) and 25 ng/ml mouse recombinant IL-6 (Peprotech) for 3 days.…”

Section: In Vitro T-cell Differentiationmentioning

confidence: 99%

The Heparan Sulfate Mimetic PG545 Modulates T Cell Responses and Prevents Delayed-Type Hypersensitivity

et al. 2020

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The heparan sulfate mimetic PG545 (pixatimod) is under evaluation as an inhibitor of angiogenesis and metastasis including in human clinical trials. We have examined the effects of PG545 on lymphocyte phenotypes and function. We report that PG545 treatment suppresses effector T cell activation and polarizes T cells away from Th17 and Th1 and toward Foxp3+ regulatory T cell subsets in vitro and in vivo. Mechanistically, PG545 inhibits Erk1/2 signaling, a pathway known to affect both T cell activation and subset polarization. Interestingly, these effects are also observed in heparanase-deficient T cells, indicating that PG545 has effects that are independent of its role in heparanase inhibition. Consistent with these findings, administration of PG545 in a Th1/Th17-dependent mouse model of a delayed-type hypersensitivity led to reduced footpad inflammation, reduced Th17 memory cells, and an increase in FoxP3+ Treg proliferation. PG545 also promoted Foxp3+ Treg induction by human T cells. Finally, we examined the effects of other heparan sulfate mimetics PI-88 and PG562 on lymphocyte polarization and found that these likewise induced Foxp3+ Treg in vitro but did not reduce Th17 numbers or improve delayed-type hypersensitivity in this model. Together, these data indicate that PG545 is a potent inhibitor of Th1/Th17 effector functions and inducer of FoxP3+ Treg. These findings may inform the adaptation of PG545 for clinical applications including in inflammatory pathologies associated with type IV hypersensitivity responses.

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“…Consequently, Map3k14 ablation conferred full resistance to EAE. In contrast, experiments using animals with a non-processable form of p100 or with constitutive activation of RelB, suggested that RelB could directly inhibit TH17 differentiation 29 , 30 . In line with this, Relb –/– T cells, though they may have an impaired TH1 differentiation ability in vitro 31 , induced severe EAE upon transfer to immunodeficient recipients, associated with enhanced TH17 cytokines in the inflamed CNS 8 .…”

Section: Introductionmentioning

confidence: 99%

A T cell-intrinsic function for NF-κB RelB in experimental autoimmune encephalomyelitis

Lalle

Lautraite

Voisin

et al. 2021

Sci Rep

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NF-kappaB (NF-κB) is a family of transcription factors with pleiotropic functions in immune responses. The alternative NF-κB pathway that leads to the activation of RelB and NF-κB2, was previously associated with the activation and function of T cells, though the exact contribution of these NF-κB subunits remains unclear. Here, using mice carrying conditional ablation of RelB in T cells, we evaluated its role in the development of conventional CD4+ T (Tconv) cells and their function in autoimmune diseases. RelB was largely dispensable for Tconv cell homeostasis, activation and proliferation, and for their polarization toward different flavors of Thelper cells in vitro. Moreover, ablation of RelB had no impact on the capacity of Tconv cells to induce autoimmune colitis. Conversely, clinical severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS) was significantly reduced in mice with RelB-deficient T cells. This was associated with impaired expression of granulocyte–macrophage colony-stimulating factor (GM-CSF) specifically in the central nervous system. Our data reveal a discrete role for RelB in the pathogenic function of Tconv cells during EAE, and highlight this transcription factor as a putative therapeutic target in MS.

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RelB regulates Th17 differentiation in a cell-intrinsic manner

Cited by 8 publications

References 35 publications

Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis

Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis

The Heparan Sulfate Mimetic PG545 Modulates T Cell Responses and Prevents Delayed-Type Hypersensitivity

A T cell-intrinsic function for NF-κB RelB in experimental autoimmune encephalomyelitis

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