3 years ago

Peptide–MHC-based nanomedicines for autoimmunity function as T-cell receptor microclustering devices

Peptide–MHC-based nanomedicines for autoimmunity function as T-cell receptor microclustering devices
Channakeshava Sokke Umeshappa, Fayi Song, Matthias Amrein, Warren C. W. Chan, Jun Yamanouchi, Xavier Clemente-Casares, Shang Wan Liu, César Fandos, Pere Santamaria, Robert Tanguay, Qin Dai, Patricia Solé, Susan Newbigging, Roopa Hebbandi Nanjundappa, Antonio Clemente, Kun Shao, Santiswarup Singha, Pascal Detampel, Jesús Blanco, Anmar Khadra, Pau Serra, Yang Yang
We have shown that nanoparticles (NPs) can be used as ligand-multimerization platforms to activate specific cellular receptors in vivo. Nanoparticles coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHC) blunted autoimmune responses by triggering the differentiation and expansion of antigen-specific regulatory T cells in vivo. Here, we define the engineering principles impacting biological activity, detail a synthesis process yielding safe and stable compounds, and visualize how these nanomedicines interact with cognate T cells. We find that the triggering properties of pMHC–NPs are a function of pMHC intermolecular distance and involve the sustained assembly of large antigen receptor microclusters on murine and human cognate T cells. These compounds show no off-target toxicity in zebrafish embryos, do not cause haematological, biochemical or histological abnormalities, and are rapidly captured by phagocytes or processed by the hepatobiliary system. This work lays the groundwork for the design of ligand-based NP formulations to re-program in vivo cellular responses using nanotechnology.

Publisher URL: http://dx.doi.org/10.1038/nnano.2017.56

DOI: 10.1038/nnano.2017.56

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