Anti-TREM2 CAR Regulatory T Cells: Engineering Targeted Immunotherapy to Modulate Microglial Polarization in Alzheimer's Disease

Alzheimer’s disease (AD) involves not only protein aggregation but also profound dysregulation of innate immunity, particularly microglial function. This project aims to develop a first‑in‑class immunotherapy that targets this axis by harnessing regulatory T cells (Tregs). We hypothesize that adoptive transfer of Tregs engineered with a chimeric antigen receptor (CAR) specific for TREM2 will restore a protective microglial phenotype, enhance amyloid‑β (Aβ) clearance, and reduce neuroinflammation. To address whether human Tregs can reprogramme microglia in an AD‑relevant context, we will use co‑culture systems combining GMP‑expanded human Tregs with iPSC‑derived microglia exposed to Aβ. Functional readouts will assess microglial activation, cytokine production, oxidative stress, and Aβ uptake. Transcriptomic and metabolic profiling will define the mechanisms by which Tregs influence microglial phenotype and function. Building on this, Tregs will be engineered to express anti‑TREM2 CARs to enhance antigen‑specific targeting and activity within the disease environment. Using established lentiviral platforms, we will optimise CAR design and evaluate Treg stability, activation, and suppressive function. Overall, this work will provide proof‑of‑concept for a novel strategy linking systemic immune regulation to CNS innate immunity, laying the foundation for targeted immunotherapies in AD.

People

	Name	Telephone	Email	Office
	Dr Cristiano Scotta Lecturer in Biosciences T: +44 (0)1895 265727 E: cristiano.scotta@brunel.ac.uk	+44 (0)1895 265727	cristiano.scotta@brunel.ac.uk	Heinz Wolff 129