In vivo engineering of immunosuppressive T cells to treat ocular autoimmune diseases.

Ocular autoimmune diseases, marked by localized inflammation and tissue remodelling, often culminate in irreversible vision loss. Conventional therapies relying on systemic immunosuppression or receptor-blocking antibodies provide sub-optimal effects. Here we assess an in vivo T-cell engineering platform that harnesses a T cell-targeted integration-deficient lentiviral vector (T-IDLE) to reprogram endogenous T cells into regulatory T (Treg)-like cells for treating experimental autoimmune uveitis (EAU) and Graves' ophthalmopathy (GO). The T-IDLE platform was engineered using a mutated cocal glycoprotein envelope to deliver Foxp3 mRNA. T-IDLEFoxp3 efficiently transduced primary T cells without impairing viability, yielding a transcriptome akin to that of natural Tregs. In vitro, these Treg-like cells exerted ratio-dependent suppression of effector T-cell proliferation, coupled with sustained secretion of TGF-β1 and IL-10. In vivo, systemic administration induced stable FOXP3 expression selectively in CD3+ T cells. In the EAU model, T-IDLEFoxp3 markedly reduced Th1 and Th17 populations, lowered clinical fundus scores, and mitigated retinal inflammatory damage. In the GO model, treatment attenuated orbital protrusion, retrobulbar adipogenesis, and fibrosis. Safety evaluations revealed no systemic toxicity or haematological perturbations. Overall, in vivo reprogramming of endogenous T cells into Treg-like cells via T-IDLEFoxp3 offers a novel, safe strategy for ocular autoimmunity, circumventing the constraints of adoptive cell transfer while restoring immune homeostasis.