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

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 Tnfaip3 fl/fl xClec9a +/cre (Tnfaip3 DNGR1−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 Tnfaip3 DNGR1−KO livers harbored an activated phenotype. Specifically, the costimulatory molecule CD40 in liver cDCs and moDCs was regulated by A20/Tnfaip3 expression. Livers from Tnfaip3 DNGR1−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 Tnfaip3 DNGR1−KO mice recognized selfproteins, 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.

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

“…160 B cell-specific knockout mice exhibit mild autoimmune disease, whereas dendritic cell specific deletion of A20 induces severe spontaneous inflammation. [161][162][163] 5.4 RELA proto-oncogene RELA (p65) is a NF-B family members that together with NFKB1 it constitutes the predominant canonical NF-B dimer. 7 The NFKB1/RELA heterodimer is also the primary target of I B , ensuring its cytoplasmic localization and thereby its inert state.…”

“…In mice, A20‐deficiency causes NF‐κB overactivation and leads to multiorgan inflammation and early lethality 160 . B cell‐specific knockout mice exhibit mild autoimmune disease, whereas dendritic cell specific deletion of A20 induces severe spontaneous inflammation 161‐163 …”

Long Noncoding RNA and Circular RNA Expression Profiles of Monocyte-Derived Dendritic Cells in Autoimmune Hepatitis

“…A series of studies have found that DCs participate in liver diseases. Das found that deletion of A20/Tnfaip3 in dendritic cells could promote autoimmune liver pathology to alter T and B-cell homeostasis ( Das et al, 2019 ). Tan et al (2020) demonstrated that hepatic DCs may trigger AIH via a deficiency in canonical Wnt/β-catenin signaling.…”

A20 deficiency in myeloid cells deteriorates the onset of vitiligo in mice

“…A20, the protein encoded by tumor necrosis factor α induced protein 3 ( TNFAIP3 ), can function as a ubiquitin‐editing enzyme (ubiquitin ligase or deubiquitinase) to inhibit nuclear factor kappa‐B (NF‐κB) activation or tumor necrosis factor (TNF)‐mediated NF‐κB independent apoptosis 7,8 . Mice harboring targeted cell‐specific (macrophages, T cells, and B cells) Tnfaip3 deletions will spontaneously develop autoinflammation, which resembles human autoimmune disease 9‐11 . Interferon‐gamma (IFN‐γ) mediated autoreactive CD8 + T cell accumulation is required for epidermal depigmentation.…”