Tolerogenic Vaccination Reduced Effector Memory CD4 T Cells and Induced Effector Memory Treg Cells for Type I Diabetes Treatment

Jingyao Zhang,Yongliang Zhang,Jingjing Kang,Yanxin Hu,Wenjuan Gao,Xu Yang,Guoliang Xia,Youmin Kang,Qirui Guo,Ciriaco A. Piccirillo

doi:10.1371/journal.pone.0070056

Jingyao Zhang, Yongliang Zhang + Show 8 more

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https://doi.org/10.1371/journal.pone.0070056

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Abstract

BackgroundVaccination could induce immune tolerance and protected NOD mice from the development of type I diabetes (T1D). We previously demonstrated that insulin peptide (B9-23) combined with dexamethasone (DEX) stimulated the expansion of antigen specific regulatory T (Treg) cells which in turn effectively prevented T1D in NOD mice. Here, we aimed to investigate the therapeutic effect of tolerogenic vaccination for T1D treatment.Methodology/Principal FindingsThe diabetic NOD mice (Blood glucose level ≧250 mg/dl) were treated with B9-23 and DEX twice. The tolerance was restored by blocking maturation of dendritic cells (DCs) and inducing Treg cells in treated NOD mice. Remarkably, the reduction of autoreactive effector memory CD4 T (Tm) cells and the induction of functional effector memory Treg (mTreg) cells contributed to the improvement of T1D in treated NOD mice.Conclusions/SignificanceTolerogenic vaccination restored tolerance and ameliorated T1D by suppressing effector CD4 Tm cells and inducing effector mTreg cells. Our findings implicate the potential of tolerogenic vaccination for T1D treatment.

Highlights

T1D results from a chronic destruction of insulin-producing b cells, presumably mediated by autoreactive CD4 T cells [1]
Our results demonstrate that tolerogenic treatment restored tolerance and ameliorated T1D by reducing CD4 Tm cells and producing activated and memory T regulatory cells
The lowest level of infiltration was noted in pancreas of mice treated with B9-23/DEX compared with other groups

Summary

Introduction

T1D results from a chronic destruction of insulin-producing b cells, presumably mediated by autoreactive CD4 T cells [1]. Autoreactive T cells are important mediators of T1D and have been shown to be antigen-specific Tm cells targeting islet antigen in T1D patients [3]. Self-antigen specific Tm cells were observed in diabetic patients, but not in healthy individuals [4]. When naive T lymphocytes are antigen activated, the expressions of several adhesion and homing molecules increase or decrease, leading to an activated effector memory cell phenotype of CD44HighCD62LLow [5]. In T1D mice, isletinfiltrating cells were characterized as CD44HighCD62LLow which appeared to be memory cells and able to transfer insulitis and diabetes [6]. We previously demonstrated that insulin peptide (B9-23) combined with dexamethasone (DEX) stimulated the expansion of antigen specific regulatory T (Treg) cells which in turn effectively prevented T1D in NOD mice. We aimed to investigate the therapeutic effect of tolerogenic vaccination for T1D treatment

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