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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Extended data figures
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.