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

Abstract

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.

Improving Vaccine and Immunotherapy Design Using Biomaterials

“…In particular, mice with EAE exhibit greater therapeutic effects when infused with a higher number of QDs displaying lower densities of self-antigen compared with fewer QDs each displaying a higher density of self-antigen. In a different mechanistic study, NPs coated with self-antigens bound to MHC-II molecules were used to directly engage T cell receptors (i.e., without APC interaction) [82,83]. This approach expanded antigen-specific T regulatory (Treg) cell levels in mouse models of MS, diabetes, and arthritis.…”

“…This approach expanded antigen-specific T regulatory (Treg) cell levels in mouse models of MS, diabetes, and arthritis. Importantly, the work revealed molecular features impacting T cell fate, with the dose of peptide: MHC controlling the degree of T cell expansion, while the density of the complexes on the NP surface dictated the extent of polarization to Treg cells [83]. Thus for both strategies targeting APCs [79] or T cells [83], design features such as display density play a crucial role – parameters difficult or impossible to control with traditional therapies.…”

Tolerogenic Nanoparticles to Treat Islet Autoimmunity

“…2). One approach made use of iron oxide nanoparticles coated with major histocompatibility complex (MHC) class I or II molecules loaded with peptides related to autoimmune disease [104, 105••, 106]. This resulted in the expansion of cognate cells with regulatory potential present as part of a negative feedback loop in response to the autoantigen [104] or conversion of effector/memory T cells into regulatory T R 1-like cells [105••].…”

“…Both the MHC I and MHC II approach were also tested in models of T1D [104, 105••], as will be described in the next section. An added benefit is that the degradation of the iron oxide particles will fold into natural iron metabolism pathways and, indeed, initial tests show that the particles have low potential for dangerous side effects [106] and do not suppress the ability of the immune system to clear a pathogen [105••]. …”

“…Bottom : gold nanoparticles decorated with both antigen and AhR ligand [111, 112••]. b Iron oxide nanoparticles coated with peptide-MHC that interact directly with T cells to expand autoregulatory cell populations [104, 105••, 106]. APC antigen presenting cell, PLG poly(lactide-co-glycolide), AhR aryl hydrocarbon receptor, MHC major histocompatibility complex…”