DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology

Tridib Das, Ingrid M. Bergen, Thomas Koudstaal, Jennifer A.C. van Hulst, Geert van Loo, André Boonstra, Thomas Vanwolleghem, Patrick S Leung, M. Eric Gershwin, Rudi W. Hendriks, Mirjam Kool

Research output: Contribution to journalArticle

Abstract

Dendritic cells (DCs)are central regulators of tolerance versus immunity. The outcome depends amongst others on DC subset and activation status. Whereas CD11b+ type 2 conventional DCs (cDC2s)initiate proinflammatory helper T (Th)-cell responses, CD103+ cDC1s are crucial for regulatory T-cell (Treg)induction and CD8+ T-cell activation. DC activation is controlled by the transcription factor NF-κB. Ablation of A20/Tnfaip3, a critical regulator of NF-κB activation, in DCs leads to constitutive DC activation and development of systemic autoimmunity. We hypothesized that the activation status of cDCs controls the development of autoimmunity. To target cDCs, DNGR1(Clec9a)-cre-mediated excision of A20/Tnfaip3 was used through generation of Tnfaip3fl/flxClec9a+/cre (Tnfaip3DNGR1−KO)mice. Immune cell activation was evaluated at 31-weeks of age. We found that DNGR1-cre-mediated deletion of A20/Tnfaip3 resulted in liver pathology characterized by inflammatory infiltrates adjacent to the portal triads. Both cDC subsets as well as monocyte-derived DCs (moDCs)in Tnfaip3DNGR1−KO livers harbored an activated phenotype. Specifically, the costimulatory molecule CD40 in liver cDCs and moDCs was regulated by A20/Tnfaip3 expression. Livers from Tnfaip3DNGR1−KO mice had augmented proportions of Th1, Th17, Treg, and follicular Th (Tfh)-cells compared to control mice, accompanied by an increase in IgA-producing plasma cells. Serum IgA from Tnfaip3DNGR1−KO mice recognized self-proteins, specifically cytoplasmic proteins in liver periportal regions. These data show that enhanced activation of cDCs and moDCs, due to A20/Tnfaip3 ablation, promotes the development of organ-specific autoimmunity but not systemic autoimmunity. This model could be useful to examine the pathobiological processes contributing to autoimmune liver diseases.

Original languageEnglish (US)
JournalJournal of autoimmunity
DOIs
StatePublished - Jan 1 2019

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Dendritic Cells
Homeostasis
B-Lymphocytes
Pathology
Autoimmunity
Liver
Monocytes
Immunoglobulin A
Central Tolerance
Regulatory T-Lymphocytes
Helper-Inducer T-Lymphocytes
Plasma Cells
Autoimmune Diseases
Liver Diseases
Immunity
Proteins
Transcription Factors
T-Lymphocytes
Phenotype
Serum

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology. / Das, Tridib; Bergen, Ingrid M.; Koudstaal, Thomas; van Hulst, Jennifer A.C.; van Loo, Geert; Boonstra, André; Vanwolleghem, Thomas; Leung, Patrick S; Gershwin, M. Eric; Hendriks, Rudi W.; Kool, Mirjam.

In: Journal of autoimmunity, 01.01.2019.

Research output: Contribution to journalArticle

Das, Tridib ; Bergen, Ingrid M. ; Koudstaal, Thomas ; van Hulst, Jennifer A.C. ; van Loo, Geert ; Boonstra, André ; Vanwolleghem, Thomas ; Leung, Patrick S ; Gershwin, M. Eric ; Hendriks, Rudi W. ; Kool, Mirjam. / DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology. In: Journal of autoimmunity. 2019.
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abstract = "Dendritic cells (DCs)are central regulators of tolerance versus immunity. The outcome depends amongst others on DC subset and activation status. Whereas CD11b+ type 2 conventional DCs (cDC2s)initiate proinflammatory helper T (Th)-cell responses, CD103+ cDC1s are crucial for regulatory T-cell (Treg)induction and CD8+ T-cell activation. DC activation is controlled by the transcription factor NF-κB. Ablation of A20/Tnfaip3, a critical regulator of NF-κB activation, in DCs leads to constitutive DC activation and development of systemic autoimmunity. We hypothesized that the activation status of cDCs controls the development of autoimmunity. To target cDCs, DNGR1(Clec9a)-cre-mediated excision of A20/Tnfaip3 was used through generation of Tnfaip3fl/flxClec9a+/cre (Tnfaip3DNGR1−KO)mice. Immune cell activation was evaluated at 31-weeks of age. We found that DNGR1-cre-mediated deletion of A20/Tnfaip3 resulted in liver pathology characterized by inflammatory infiltrates adjacent to the portal triads. Both cDC subsets as well as monocyte-derived DCs (moDCs)in Tnfaip3DNGR1−KO livers harbored an activated phenotype. Specifically, the costimulatory molecule CD40 in liver cDCs and moDCs was regulated by A20/Tnfaip3 expression. Livers from Tnfaip3DNGR1−KO mice had augmented proportions of Th1, Th17, Treg, and follicular Th (Tfh)-cells compared to control mice, accompanied by an increase in IgA-producing plasma cells. Serum IgA from Tnfaip3DNGR1−KO mice recognized self-proteins, specifically cytoplasmic proteins in liver periportal regions. These data show that enhanced activation of cDCs and moDCs, due to A20/Tnfaip3 ablation, promotes the development of organ-specific autoimmunity but not systemic autoimmunity. This model could be useful to examine the pathobiological processes contributing to autoimmune liver diseases.",
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AU - Bergen, Ingrid M.

AU - Koudstaal, Thomas

AU - van Hulst, Jennifer A.C.

AU - van Loo, Geert

AU - Boonstra, André

AU - Vanwolleghem, Thomas

AU - Leung, Patrick S

AU - Gershwin, M. Eric

AU - Hendriks, Rudi W.

AU - Kool, Mirjam

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