Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4+ T cell type 1 (TR1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into TR1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.

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We thank S. Thiessen, J. DeLongchamp, J. Erickson, J. Luces, R. Barasi and K. Umeshappa for technical contributions; L. Kennedy, L. Robertson and Y. Liu for flow cytometry; F. Jirik for help with histological analyses of arthritic mice; J. Elliott and K. Suzuki for Meso Scale measurements; M. Fritzler for Luminex; and P. Colarusso for assistance with microscopy. This work was funded by the Canadian Institutes of Health Research (CIHR), the Diabetes Research Foundation, the Juvenile Diabetes Research Foundation (JDRF), the Canadian Diabetes Association (CDA), the Multiple Sclerosis Society of Canada (MSSC), the Brawn Family Foundation, National Research Council of Canada–Industrial Research Assistance Program (NRC-IRAP), Instituto de Investigaciones Sanitarias Carlos III (ISCIII) Integrated Projects of Excellence and FEDER, the Ministerio de Economia y Competitividad of Spain (MINECO), the European Association for the study of diabetes (EASD), the Sardà Farriol Research Programme, and the European Community’s Seventh Framework Programme. X.C.C. was supported by studentships from the AXA Research Fund and the endMS network. P.A. was supported by the endMS network. J.B. was suported by a Rio Hortega fellowship and by a grant from the Spanish Society for Diabetes. S.T. was supported by a studentship from the Alberta Heritage Foundation of Medical Research (AHFMR). J.W. was funded by a fellowship from the CDA. P.Se. is an investigator of the Ramon y Cajal reintegration program and is supported by a JDRF Career Development Award. P.Sa. is a Scientist of the Alberta Innovates-Health Solutions and a scholar of ISCIII. The JMDRC is supported by the Diabetes Association (Foothills) and the CDA.

Author information

Author notes

    • Jesus Blanco
    • , Poornima Ambalavanan
    • , Jun Yamanouchi
    •  & Santiswarup Singha

    These authors contributed equally to this work.


  1. Julia McFarlane Diabetes Research Centre (JMDRC), and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada

    • Xavier Clemente-Casares
    • , Poornima Ambalavanan
    • , Jun Yamanouchi
    • , Santiswarup Singha
    • , Sue Tsai
    • , Jinguo Wang
    • , Yang Yang
    •  & Pere Santamaria
  2. Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain

    • Jesus Blanco
    • , Cesar Fandos
    • , Pau Serra
    •  & Pere Santamaria
  3. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid 28029, Spain

    • Jesus Blanco
  4. Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona 08028, Spain

    • Nahir Garabatos
    • , Cristina Izquierdo
    •  & Thomas Stratmann
  5. Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada

    • Smriti Agrawal
    • , Michael B. Keough
    •  & V. Wee Yong
  6. Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101-2795, USA

    • Eddie James
  7. Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA

    • Anna Moore
  8. Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada

    • Yang Yang


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X.C.-C. executed most of the experiments in Figs 1, 3a–d, h–j, 4a–f, Supplementary Table 1 and Extended Data Figs 1b–n, 2, 3, 5a–f, n–t 6, with contributions from J.Y., P.A., S.T. and J.W., and contributed to writing the manuscript with P.Sa. J.Y. executed the experiments in Figs 3e–g, 4g–i and Extended Data Figs 1a, c–f, 2h and 5u, v. P.A. executed all of the experiments described in Figs. 2, 3b, and Extended Data Figs 4 and 5g–m. J.B. recruited T1D patients and healthy controls and performed the experiments leading to Fig. 5, Extended Data Fig. 7 and Supplementary Table 2 under the supervision of P.Se. S.S., Y.Y. and A.M. produced nanoparticles and pMHC–NP conjugates for the study. C.F. produced 2.5mi/IAg7 class II monomers for mechanistic experiments. S.A. and M.K. contributed to the execution of the EAE experiments, and analysed histological sections for histopathological features of CNS inflammation and demyelination under the supervision of V.W.Y. E.J. provided human T1D-relevant pMHC class II monomers and tetramers. N.G., C.I. and T.S. produced the pMHC class II monomers used for the studies on the reversal of T1D. P.Sa. designed the study, supervised and coordinated its execution and wrote the manuscript.

Competing interests

P.Sa. is the scientific founder of Parvus Therapeutics Inc. and has a financial interest in the company.

Corresponding author

Correspondence to Pere Santamaria.

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  1. 1.

    Supplementary Tables 1 and 2

    This file comprises: Table 1 - Transcriptional profile of pMHC-NP-expanded CD4+ T-cells. (a) qRT-PCR for a panel of 384 immunological markers in 2.5mi/IAg7 tetramer+ versus tetramer CD4+ T-cells sorted from NOD mice treated with 10 doses of 2.5mi/IAg7-NPs from 10-15 weeks of age (n=3 and 4 samples, respectively). The cells were stimulated in vitro with anti-CD3/anti-CD28 mAb-coated Dynabeads before RNA collection. Panel summarizes the most significant differences. (b) qRT-PCR for 8 TR1-relevant markers, including markers that were not represented in the primer set used in a. Data correspond to four additional 2.5mi/IAg7 tetramer+ and seven tetramer CD4+ T-cell samples; Table 2 - Human T1D donors and outcome of pMHC-NP, peptide, peptide-NP and peptide-MP therapy in PBMC-engrafted NSG hosts. See text for details.

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