CAR T cell targeting of inflammatory myeloid progenitors in the bone marrow remodels border-associated macrophages and reverses cognitive aging

Harris, Alexander S, Rouse, James A, Guo, Guangran, Fernandez-Maestre, Inés, Pal, Sujay, Oh, Brian, Li, Shuxuan, See, Wen Yi, Anderson, Arianna, Gewolb, Joseph, Soethout, Matthew, Habel, Jill, Utama, Rad, Vakoc, Christopher R, Amor, Corina (September 2026) CAR T cell targeting of inflammatory myeloid progenitors in the bone marrow remodels border-associated macrophages and reverses cognitive aging. bioRxiv. ISSN 2692-8205 (Submitted)

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Abstract

Aging is associated with progressive neuroinflammation and cognitive decline, yet the cellular sources that sustain this process and whether they can be targeted peripherally remain unclear. Here, we identify inflammatory border-associated macrophages (BAMs) as key drivers of neuroinflammation in aging and show that their therapeutic and prophylactic elimination through intrathecal CAR T cell therapy restores cognitive performance in mouse models of aging and Alzheimer’s disease. Furthermore, targeting of aged inflammatory bone marrow myeloid progenitors through either intravenous CAR T cells, which do not infiltrate the brain, or through transplantation of CAR T-treated progenitors is sufficient to reduce neuroinflammation and cognitive impairment. These findings reveal that bone marrow myeloid progenitors harbor a heritable inflammatory transcriptional state that is transmitted to their BAM progeny, driving neuroinflammation and cognitive deterioration, and conserved in human aging. Critically, this proinflammatory state is marked by the upregulation of surface proteins, enabling precise peripheral CAR T cell targeting of these progenitors for long-lasting therapeutic effects in cognitive aging.

Item Type:	Paper
Subjects:	organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions
CSHL Authors:	Habel, Jill Utama, Raditya Vakoc, Christopher R. Amor, Corina Harris, Alexander Rouse, James Guo, Guangran Fernandez Maestre, Ines Pal, Sujay Oh, Brian Li, Shuxuan See, Wen Yi Anderson, Arianna Gewolb, Joseph Soethout, Matthew
Communities:	CSHL labs > Koo Lab CSHL labs > Vakoc lab CSHL labs > Amor lab CSHL Post Doctoral Fellows
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	28 September 2026
Date Deposited:	08 Oct 2026 19:20
Last Modified:	08 Oct 2026 19:20
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42337

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