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Watts, D. ; Janßen, M. ; Jaykar, M.* ; Palmucci, F. ; Weigelt, M.* ; Petzold, C.* ; Hommel, A.* ; Sparwasser, T.* ; Bonifacio, E. ; Kretschmer, K.

Transient depletion of Foxp3+ regulatory T cells selectively promotes aggressive β cell autoimmunity in genetically susceptible DEREG mice.

Front. Immunol. 12:720133 (2021)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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Type 1 diabetes (T1D) represents a hallmark of the fatal multiorgan autoimmune syndrome affecting humans with abrogated Foxp3+ regulatory T (Treg) cell function due to Foxp3 gene mutations, but whether the loss of Foxp3+ Treg cell activity is indeed sufficient to promote β cell autoimmunity requires further scrutiny. As opposed to human Treg cell deficiency, β cell autoimmunity has not been observed in non-autoimmune-prone mice with constitutive Foxp3 deficiency or after diphtheria toxin receptor (DTR)-mediated ablation of Foxp3+ Treg cells. In the spontaneous nonobese diabetic (NOD) mouse model of T1D, constitutive Foxp3 deficiency did not result in invasive insulitis and hyperglycemia, and previous studies on Foxp3+ Treg cell ablation focused on Foxp3DTR NOD mice, in which expression of a transgenic BDC2.5 T cell receptor (TCR) restricted the CD4+ TCR repertoire to a single diabetogenic specificity. Here we revisited the effect of acute Foxp3+ Treg cell ablation on β cell autoimmunity in NOD mice in the context of a polyclonal TCR repertoire. For this, we took advantage of the well-established DTR/GFP transgene of DEREG mice, which allows for specific ablation of Foxp3+ Treg cells without promoting catastrophic autoimmune diseases. We show that the transient loss of Foxp3+ Treg cells in prediabetic NOD.DEREG mice is sufficient to precipitate severe insulitis and persistent hyperglycemia within 5 days after DT administration. Importantly, DT-treated NOD.DEREG mice preserved many clinical features of spontaneous diabetes progression in the NOD model, including a prominent role of diabetogenic CD8+ T cells in terminal β cell destruction. Despite the severity of destructive β cell autoimmunity, anti-CD3 mAb therapy of DT-treated mice interfered with the progression to overt diabetes, indicating that the novel NOD.DEREG model can be exploited for preclinical studies on T1D under experimental conditions of synchronized, advanced β cell autoimmunity. Overall, our studies highlight the continuous requirement of Foxp3+ Treg cell activity for the control of genetically pre-installed autoimmune diabetes.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Foxp3 ; Treg Cells ; Cell Ablation ; Immune Regulation ; Type 1 Diabetes; Nonobese Diabetic Mice; Invariant Nkt Cells; Monoclonal-antibody; Polyendocrinopathy; Enteropathy; Protection; Tolerance; Insulitis; Requires; Mouse
ISSN (print) / ISBN 1664-3224
e-ISSN 1664-3224
Journal Frontiers in Immunology
Quellenangaben Volume: 12, Issue: , Pages: , Article Number: 720133 Supplement: ,
Publisher Frontiers
Publishing Place Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Pancreatic Islet Research (IPI)
Grants BMBF (German Ministry for Education and Research)
CRTD/Center for Regenerative Therapies Dresden, DFG