Extended Data Figure 8: Schematic of the proposed mode of operation of pMHCII-based nanomedicines.

pMHCII-coated NPs (pMHC–NP, lacking costimulatory molecules) promote the differentiation of disease-primed (antigen-experienced) IFNγ-producing CD4⁺ T_H1-cells into memory T_R1-like CD4⁺ T cells followed by systemic expansion. This differentiation process (but not the subsequent expansion) requires both IFNγ and IL-10, whereas IL-27 is dispensable. The pMHC–NP-expanded (mono-specific) autoreactive T_R1-like CD4⁺ T cells then suppress other autoreactive T-cell responses by secreting IL-21, IL-10 and TGF-β, which act on local APCs (B cells, CD11c⁺ and CD11b⁺ cells) that have captured the cognate autoantigen and thus present cognate pMHCII complexes to the expanded T_R1-like cells. This interaction inhibits the proinflammatory function of the targeted APCs and blocks their ability to present other pMHC class I and class II complexes to non-pMHC–NP-cognate autoreactive T-cell specificities (note that the local APCs uptake both cognate and non-cognate autoantigens shed into the milieu simultaneously). Suppression of antigen-presentation requires IL-10 and TGF-β but not IFNγ or IL-21. Furthermore, cognate interactions between the pMHC–NP-expanded T_R1 CD4⁺ T cells and autoreactive B cells specific for the cognate autoantigen (able to display the cognate pMHCII complex on the surface) promotes their differentiation into B_reg cells in an IL-21-dependent manner, which contribute to promote local immunosuppression, likely by secreting IL-10. Suppression of antigen presentation selectively targets APCs displaying the cognate pMHC, but as local APCs that capture the cognate autoantigen also capture other autoantigens simultaneously, the autoregulatory CD4⁺ T cells expanded by pMHC–NPs blunt the presentation of other autoantigenic pMHC complexes to a broad range of autoreactive T cells. This suppression is disease-specific and self-limiting.