, Volume 60, Issue 12, pp 2418–2431 | Cite as

Multipeptide-coupled nanoparticles induce tolerance in ‘humanised’ HLA-transgenic mice and inhibit diabetogenic CD8+ T cell responses in type 1 diabetes

  • Xinyu Xu
  • Lingling Bian
  • Min Shen
  • Xin Li
  • Jing Zhu
  • Shuang Chen
  • Lei Xiao
  • Qingqing Zhang
  • Heng Chen
  • Kuanfeng Xu
  • Tao Yang



Induction of antigen-specific immunological tolerance may provide an attractive immunotherapy in the NOD mouse model but the conditions that lead to the successful translation to human type 1 diabetes are limited. In this study, we covalently linked 500 nm carboxylated polystyrene beads (PSB) with a mixture of immunodominant HLA-A*02:01-restricted epitopes (peptides-PSB) that may have high clinical relevance in humans as they promote immune tolerance; we then investigated the effect of the nanoparticle–peptide complexes on T cell tolerance.


PSB-coupled mixtures of HLA-A*02:01-restricted epitopes were administered to HHD II mice via intravenous injection. The effects on delaying the course of the disease were verified in NOD.β2m null HHD mice. The diabetogenic HLA-A*02:01-restricted cytotoxic lymphocyte (CTL) responses to treatment with peptides-PSB were validated in individuals with type 1 diabetes.


We showed that peptides-PSB could induce antigen-specific tolerance in HHD II mice. The protective immunological mechanisms were mediated through the function of CD4+CD25+ regulatory T cells, suppressive T cell activation and T cell anergy. Furthermore, the peptides-PSB induced an activation and accumulation of regulatory T cells and CD11c+ dendritic cells through a rapid production of CD169+ macrophage-derived C-C motif chemokine 22 (CCL22). Peptides-PSB also prevented diabetes in ‘humanised’ NOD.β2m null HHD mice and suppressed pathogenic CTL responses in people with type 1 diabetes.


Our findings demonstrate for the first time the potential for using multipeptide-PSB complexes to induce T cell tolerance and halt the autoimmune process. These findings represent a promising platform for an antigen-specific tolerance strategy in type 1 diabetes and highlight a mechanism through which metallophilic macrophages mediate the early cell–cell interactions required for peptides-PSB-induced immune tolerance.


Antigen-specific tolerance Humanised mice Immunotherapy Nanoparticles Type 1 diabetes 



Antigen-conjugated apoptotic splenocyte


Antigen-presenting cell


C-C motif chemokine 22


C-C chemokine receptor type 4


Complete Freund’s adjuvant


Carboxyfluorescein diacetate succinimidyl ester




Cytotoxic lymphocyte


Dendritic cell


Ethylene carbodiimide


Human immunodeficiency virus


Incomplete Freund’s adjuvant


Islet-specific glucose-6-phosphatase catalytic subunit-related protein


Macrophage receptor with collagenous structure



Metallophilic macrophage


Marginal zone


Marginal zone macrophage


Peripheral blood mononuclear cells


Polystyrene beads


Spot-forming cells


T helper


Regulatory T cell


Zinc transporter-8



We thank F. Lemonnier (Institute Pasteur, Paris) for providing the HHD II mice.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.


This study was supported by grants from the National Natural Science Foundation of China (number 81400808, 81530026 and 81270897) and a Project Funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

All authors conceived and designed the study. XYX and LLB contributed to acquisition, analysis and interpretation of data. XYX and TY wrote the first draft of the manuscript. All authors revised the manuscript critically and gave final approval of the submitted version. TY is the guarantor of the work.

Supplementary material

125_2017_4419_MOESM1_ESM.pdf (2.4 mb)
ESM (PDF 2420 kb)


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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Xinyu Xu
    • 1
  • Lingling Bian
    • 1
    • 2
  • Min Shen
    • 1
  • Xin Li
    • 1
  • Jing Zhu
    • 1
  • Shuang Chen
    • 1
  • Lei Xiao
    • 1
  • Qingqing Zhang
    • 1
  • Heng Chen
    • 1
  • Kuanfeng Xu
    • 1
  • Tao Yang
    • 1
  1. 1.Department of EndocrinologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingPeople’s Republic of China
  2. 2.Department of EndocrinologyYancheng City No.1 People’s HospitalYanchengPeople’s Republic of China

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