Engineered peripheral CD4 T cells delivery across the BBB promote intracerebral Treg conversion unleashes microglial phagocytotic activity for Alzheimer's disease treatment.

Alzheimer's disease (AD) affects thirty million individuals worldwide, but a viable treatment has yet to be identified. During disease progression, peripheral immune cells, including peripheral T cells, infiltrate the brain. Although CD4+ regulatory T cells have been demonstrated to exhibit neuroprotective efficacy in AD, the precise roles of these cells in the brain remain elusive. Here, we report that β-amyloid (Aβ) 1-42 antigen-specific CD4+ T cells spontaneously cross the blood-brain barrier (BBB) into the brain in an APP/PS1 mouse model. To promote parenchymal Treg conversion from infiltrated CD4+ T cells and minimize the perturbations of the brain microenvironment, we engineered an Aβ1-42 antigen-specific CD4+ T cell-based nanodelivery system to release the compound AS2863619, a CDK8/19 inhibitor (eTc-AS), which can bypass the BBB and selectively induce the conversion of CD4+ T cells into Treg cells within the brain region. These cells demonstrated notable pathological amelioration in APP/PS1 mice, in part by interacting with microglia or recruited macrophage via PD-L1/PD-1 signaling. Our study reveals valuable engineered T cell therapies and suggests an immune checkpoint mechanism underlying the neuroprotective function of the Treg-microglia like cell interplay in AD.