Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice

Akazawa, Satoru; Kobayashi, Masakazu; Kuriya, Genpei; Horie, Ichiro; Yu, Liping; Yamasaki, Hironori; Okita, Minoru; Nagayama, Yuji; Matsuyama, Tomohiro; Akbari, Masoud; Yui, Katsuyuki; Kawakami, Atsushi; Abiru, Norio

doi:10.1007/s00125-015-3724-3

Cited by 8 publications

(5 citation statements)

References 48 publications

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“…Tissue Sections (3 μm) were stained with H&E (Servicebio, Wuhan, China) or processed for staining for insulin (GB11334, Servicebio). Insulitis was scored on the basis of islet infiltration with the following grades: grade 0, no insulitis or peri-insulitis; grade 1, insulitis involving < 25% islet; grade 2, insulitis involving 25–50% islet; grade 3, insulitis involving 50–75% islet, and grade 4, insulitis involving > 75% and/or complete islet infiltration (Akazawa et al 2015 ). More than 100 islets were scored in each group.…”

Section: Methodsmentioning

confidence: 99%

Increased plasmablasts enhance T cell-mediated beta cell destruction and promote the development of type 1 diabetes

Ling

Shen

Zhang

et al. 2022

Mol Med

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Background Although type 1 diabetes (T1D) is typically described as a T cell-mediated autoimmune disease, increasing evidence for a role of B cells has emerged. However, the pivotal disease-relevant B cell subset and its contribution to islet autoimmunity remain elusive. Methods The frequencies and phenotypic characteristics of circulating B cell subsets were analyzed using flow cytometry in individuals with new-onset T1D, long-term T1D, type 2 diabetes, and nondiabetic controls, and also in a prospective cohort of patients receiving mesenchymal stromal cell (MSC) transplantation. NOD mice and adoptive transfer assay were used to dissect the role of the certain B cell subset in disease progression. An in-vitro coculture system of islets with immune cells was established to examine the response against islets and the underlying mechanisms. Results We identified that plasmablasts, a B cell subset at the antibody-secreting stage, were significantly increased and correlated with the deterioration of beta cell function in patients with new-onset T1D. Further, a fall of plasmablast number was associated with the preservation of beta cell function in patients who received MSC transplantation after 3 months of follow-up. Meanwhile, a gradual increase of plasmablasts in pancreatic lymph nodes during the natural progression of insulitis was observed in non-obese diabetic (NOD) mice; adoptive transfer of plasmablasts together with T cells from NOD mice accelerated diabetes onset in NOD/SCID recipients. Conclusions Our study revealed that plasmablasts may function as antigen-presenting cells and promote the activation and proinflammatory response of CD4+ T cells, further contributing to the T cell-mediated beta cell destruction. Our results provide insights into the pathogenic role of plasmablasts in islet autoimmunity and may offer new translational strategies for inhibiting T1D development.

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Section: Methodsmentioning

confidence: 99%

Increased plasmablasts enhance T cell-mediated beta cell destruction and promote the development of type 1 diabetes

Ling

Shen

Zhang

et al. 2022

Mol Med

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“…Mice deficient in IRF4 expression fail to develop fully functional Tmem, and lack of IRF4 expression results in Tex ( 265 , 266 ). Strikingly, NOD mice deficient in IRF4 fail to develop T1D and show dysfunctional T cell responses ( 267 ). Maintenance of long-lived Tmem responses has been tied to the pro-memory transcription factor TCF1 ( 268 – 270 ).…”

Section: The Role Of T Cell Receptor Signaling In the Maintenance Of mentioning

confidence: 99%

The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes

et al. 2021

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T cell receptor (TCR) signaling influences multiple aspects of CD4+ and CD8+ T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.

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“…As type 1 diabetes is considered to be a T‐cell‐mediated disease, 19 we analyzed the T cell composition in PLNs from Smad4 tKO and WT NOD mice at 12 weeks of age. We found that the size and total cell number of PLNs were increased in Smad4 tKO compared with WT NOD mice (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

Impact of T‐cell‐specific Smad4 deficiency on the development of autoimmune diabetes in NOD mice

Kim

Lee

2016

Immunol Cell Biol

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Type 1 diabetes results from autoimmune-mediated pancreatic beta-cell destruction and transforming growth factor-beta (TGF-β) is known to play a preventive role in type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we investigated the role of Smad4, a key molecule for Smad-dependent TGF-β signaling, in T cells of NOD mice in the pathogenesis of autoimmune diabetes. We generated T-cell-specific Smad4 knockout (Smad4 tKO) NOD mice and assessed the pathological and immunological changes. Smad4 tKO showed earlier onset and increased incidence of diabetes than wild type (WT) NOD mice. Pathological features such as insulitis, anti-glutamic acid decarboxylase auto-antibody levels and serum IFN-γ levels were significantly increased in Smad4 tKO compared with WT NOD mice. Proportion and number of activated/memory CD4+ T cell were significantly increased in pancreatic lymph nodes of Smad4 tKO compared with WT NOD mice. However, the proportion and function of regulatory T cells was not different. Effector CD4+ T cells from Smad4 tKO were more resistant to suppression by regulatory T cells than effector cells from WT NOD mice. The proliferative potential of effector T cells from Smad4 tKO was significantly elevated compared with WT NOD mice, and activation of sterol regulatory element binding protein-1c (SREBP-1c) in T cells of Smad4 tKO NOD mice was correlated with this proliferative activity. We conclude that Smad4 deletion in T cells of NOD mice accelerated the development of autoimmune diabetes and increased the incidence of the disease by dysregulation of T cell activation at least in part via SREBP-1c activation.

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Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice

Cited by 8 publications

References 48 publications

Increased plasmablasts enhance T cell-mediated beta cell destruction and promote the development of type 1 diabetes

Increased plasmablasts enhance T cell-mediated beta cell destruction and promote the development of type 1 diabetes

The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes

Impact of T‐cell‐specific Smad4 deficiency on the development of autoimmune diabetes in NOD mice

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