Type 1 diabetes vaccine candidates promote human Foxp3+Treg induction in humanized mice

Abstract

Immune tolerance is executed partly by Foxp3+regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing β-cells. The development of autoantigen-specific vaccination strategies for Foxp3+Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3+Treg-induction in vivo. We identify HLA-DQ8-restricted insulin-specific CD4+T cells and demonstrate efficient human insulin-specific Foxp3+Treg-induction upon subimmunogenic vaccination with strong agonistic insulin mimetopes in vivo. Induced human Tregs are stable, show increased expression of Treg signature genes such as Foxp3, CTLA4, IL-2Rα and TIGIT and can efficiently suppress effector T cells. Such Foxp3+Treg-induction does not trigger any effector T cells. These T1D vaccine candidates could therefore represent an expedient improvement in the challenge to induce human Foxp3+Tregs and to develop novel precision medicines for prevention of islet autoimmunity in children at risk of T1D.

miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity

“…S10 A-C). Next, to assess a potential human in vivo relevance of miRNA92a antagomir application, we investigated human HLA-DQ8-restricted insulin-specific TFH cells in humanized NOD Scid IL2 receptor gamma chain knockout (NSG) human leucocyte antigen (HLA)-DQ8 Tg mice in accordance with previously established procedures (31). Specifically, we focused on human pancreas-infiltrating CD4 + T cells upon treatment with a miRNA92a antagomir (1 wk of treatment, with injections three times per week at 10 mg/kg) or a control antagomir.…”

“…We used CD4 + T cells from nondiabetic children without autoimmunity (islet autoantibody-negative children), with recent onset of autoimmunity (recent activation, multiple autoantibodies for <5 y), persistent autoimmunity (multiple autoantibodies for >5 to <10 y), and long-term autoimmunity (multiple autoantibodies for >10 y without overt T1D). We applied recently developed fluorescent insulin-specific HLA-DQ8 tetramers (14E-22E and 14E-21G 22E tetramers) based on a set of two insulin B-chain 10-23 mimetopes to identify human HLA-DQ8-restricted insulinspecific CD4 + T cells ex vivo directly (31). We detected no tet + CD4 + T cells using the control tetramers, whereas a population of insulin-specific CD4 + T cells was readily identified ex vivo with the insulin-specific tetramers ( Fig.…”

A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes

“…S1). Given the critical role of insulin epitopes as target autoantigens, we focused on insulin-specific T reg induction using highly pure naïve CD4 + T cells and premature withdrawal of TCR stimulation after 18 hours without transforming growth factor–β (11, 12). We therefore used previously established protocols using HLA-DQ8 insulin-specific monomers coated onto streptavidin-precoated plates (12).…”

“…In contrast, high frequencies of insulin-specific T regs were associated with profound delays in progressing to symptomatic T1D (12). However, a mechanistic understanding of relevant promoters of T cell activation involved in triggering islet auto-immunity is still lacking.…”

A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children

“…Alternatively, the loss of IAA may simply be a matter of increasing age and therefore seen in children with slow progression. Nevertheless, we have recently shown that high frequencies of insulin-specific regulatory T cells are found in multiple-autoantibody-positive children who do not progress to clinical type 1 diabetes and therefore could indicate at least periods of successful ongoing immune regulation in such children [50].…”