NKT sublineage specification and survival requires the ubiquitin-modifying enzyme TNFAIP3/A20

Drennan, Michael; Govindarajan, Srinath; Verheugen, Eveline; Coquet, Jonathan M.; Staal, Jens; McGuire, Conor; Taghon, Tom; Leclercq, Georges; Beyaert, Rudi; Loo, Geert; Lambrecht, Bart N.

doi:10.1084/jem.20151065

Cited by 30 publications

(32 citation statements)

References 28 publications

(48 reference statements)

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“…demonstrated that splenic CD8 + T cells of naïve mice express A20 in vivo 32. In accordance with Giordano et al 31,.…”

Section: Discussionsupporting

confidence: 83%

“…Of note, the increased activation of T cells, which has also been detected by Giordano et al 31,. did not result in a spontaneous inflammatory disease of CD4-Cre A20 fl/fl mice (our unpublished data), which has also not been described before3132. This may be explained by the fact that cytokine production of CD4 + (IFN-γ, IL-2) and CD8 + T cells (IFN-γ, granzyme B) was not increased in naïve CD4-Cre as compared to A20 fl/fl mice.…”

Section: Discussionsupporting

confidence: 73%

“…In contrast, Drennan et al . demonstrated that A20-deficiency resulted in an increased cell death of invariant NK T cells due to apoptosis but not necroptosis32. At present, the discrepant results concerning the induction and A20-mediated regulation of apoptosis and necroptosis of CD8 + (our study), CD4 + T cells21 and invariant NK T cells32 are unresolved but may be explained by intrinsic cell-type specific differences between these two T cell subsets.…”

Section: Discussioncontrasting

confidence: 51%

“…S1a–c). The small reduction of CD4 + T cell numbers may be caused by a reduction of invariant NK T cells, since A20 is required for the development of this subset of CD4 + T cells32.…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

Just

Nishanth

Buchbinder

et al. 2016

Sci Rep

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The ubiquitin-modifying enzyme A20, an important negative feedback regulator of NF-κB, impairs the expansion of tumor-specific CD8+ T cells but augments the proliferation of autoimmune CD4+ T cells. To study the T cell-specific function of A20 in bacterial infection, we infected T cell-specific A20 knockout (CD4-Cre A20fl/fl) and control mice with Listeria monocytogenes. A20-deficient pathogen-specific CD8+ T cells expanded stronger resulting in improved pathogen control at day 7 p.i. Imaging flow cytometry revealed that A20-deficient Listeria-specific CD8+ T cells underwent increased apoptosis and necroptosis resulting in reduced numbers of memory CD8+ T cells. In contrast, the primary CD4+ T cell response was A20-independent. Upon secondary infection, the increase and function of pathogen-specific CD8+ T cells, as well as pathogen control were significantly impaired in CD4-Cre A20fl/fl mice. In vitro, apoptosis and necroptosis of Listeria-specific A20-deficient CD8+ T cells were strongly induced as demonstrated by increased caspase-3/7 activity, RIPK1/RIPK3 complex formation and more morphologically apoptotic and necroptotic CD8+ T cells. In vitro, A20 limited CD95L and TNF-induced caspase3/7 activation. In conclusion, T cell-specific A20 limited the expansion but reduced apoptosis and necroptosis of Listeria-specific CD8+ T cells, resulting in an impaired pathogen control in primary but improved clearance in secondary infection.

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“…demonstrated that splenic CD8 + T cells of naïve mice express A20 in vivo 32. In accordance with Giordano et al 31,.…”

Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 73%

Section: Discussioncontrasting

confidence: 51%

“…S1a–c). The small reduction of CD4 + T cell numbers may be caused by a reduction of invariant NK T cells, since A20 is required for the development of this subset of CD4 + T cells32.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

Just

Nishanth

Buchbinder

et al. 2016

Sci Rep

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“…Unrestricted necroptosis in A20 −/− CD4 + cells led to reduced inflammation in a Th17‐cell‐dependent model of autoimmune encephalomyelitis . In NKT1 and NKT2 natural killer T (NKT) cell sublineages, A20 was also shown to restrict TCR‐dependent activation and survival, thereby controlling NKT cell differentiation . Prompted by the apparent contrast between anti‐inflammatory effects in various tissues and cell types on one hand and promotion of T helper cell survival on the other, we tested the functionality of A20 deficient CD4 + T cells in a mouse model of T cell‐dependent acute GVHD.…”

Section: Introductionmentioning

confidence: 99%

A20 deletion in T cells modulates acute graft‐versus‐host disease in mice

et al. 2017

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The NF-κB regulator A20 limits inflammation by providing negative feedback in myeloid cells and B cells. Functional lack of A20 has been linked to several inflammatory and autoimmune diseases. To define how A20 affects the functionality of T effector cells in a highly inflammatory environment, we performed conventional allogeneic hematopoietic stem cell transplantation (allo-HSCT) with A20-deficient CD4 and CD8 donor T cells in mice. Severity and mortality of graft-versus-host disease (GVHD) after allo-HSCT was drastically reduced in recipients transplanted with conventional doses of A20-deficient T cells. Consistently, we found that the A20-deficient donor T-cell compartment was strongly diminished at various timepoints after allo-HSCT. However, proportionally more A20-deficient donor T cells produced IFN-γ and systemic inflammation was elevated early after allo-HSCT. Consequently, increasing the dose of transplanted A20-deficient T cells reversed the original phenotype and resulted in enhanced GVHD mortality compared to recipients that received A20 T cells. Still, A20-deficient T cells, activated either through T cell receptor-dependent or -independent mechanisms, were less viable than control A20 T cells, highlighting that A20 balances both, T-cell activation and survival. Thus, our findings suggest that targeting A20 in T cells may allow to modulate T-cell-mediated inflammatory diseases like GVHD.

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Deletion of Mucosa‐Associated Lymphoid Tissue Lymphoma Translocation Protein 1 in Mouse T Cells Protects Against Development of Autoimmune Arthritis but Leads to Spontaneous Osteoporosis

Gilis

Gaublomme

Staal

et al. 2019

Arthritis & Rheumatology

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Objective. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) plays a crucial role in innate and adaptive immune signaling by modulating the threshold for activation of immune cells, including Treg cells. Therefore, MALT-1 is regarded to be an interesting therapeutic target in several immune-mediated diseases. The goal of this study was to examine the role of MALT-1 in experimental animal models of rheumatoid arthritis (RA).Methods. MALT-1 activation was assessed by measuring cleavage of the deubiquitinase CYLD in lymphocytes from mice with collagen-induced arthritis (CIA). Furthermore, the impact of MALT-1 deficiency on arthritis was evaluated in Malt1 KO mice with CIA or with collagen antibody-induced arthritis (CAIA). T cell-specific MALT-1 deficiency was measured in mice with deletion of T cell-specific MALT-1 (Malt1 TcellKO ), and the timedependent effects of MALT-1 deficiency were assessed in mice with deletion of tamoxifen-inducible T cellspecific MALT-1 (Malt1 iTcellKO ). Bone density was determined in MALT-1-deficient mice using micro-computed tomography and femur-bending tests. Reconstitution of Treg cells was performed using adoptive transfer experiments.Results. MALT-1 activation was observed in the lymphocytes of mice with CIA. T cell-specific MALT-1 deletion in the induction phase of arthritis (incidence of arthritis, 25% in control mice versus 0% in Malt1 iTcellKO mice; P < 0.05), but not in the effector phase of arthritis, completely protected mice against the development of CIA. Consistent with this finding, MALT-1 deficiency had no impact on CAIA, an effector phase model of RA. Finally, mice with MALT-1 deficiency showed a spontaneous decrease in bone density (mean ± SEM trabecular thickness, 46.3 ± 0.7 μm in control mice versus 40 ± 1.1 μm in Malt1 KO mice; P < 0.001), which was linked to the loss of Treg cells in these mice.Conclusion. Overall, these data in murine models of RA highlight MALT-1 as a master regulator of T cell activation, which is relevant to the pathogenesis of autoimmune arthritis. Furthermore, these findings show that MALT-1 deficiency can lead to spontaneous osteoporosis, which is associated with impaired Treg cell numbers.

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NKT sublineage specification and survival requires the ubiquitin-modifying enzyme TNFAIP3/A20

Abstract: Drennan et al. use a new mouse to show that A20-deficient NKT cells are hyperresponsive to TCR-dependent stimuli and have severely impaired NKT cell development.

Cited by 30 publications

References 28 publications

A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

A20 deletion in T cells modulates acute graft‐versus‐host disease in mice

Deletion of Mucosa‐Associated Lymphoid Tissue Lymphoma Translocation Protein 1 in Mouse T Cells Protects Against Development of Autoimmune Arthritis but Leads to Spontaneous Osteoporosis

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