Chandelier
Senior Member (Voting Rights)
Localized PD-1 CAR T therapy reprograms neuroinflammation
• PD-1+ Tfh-like cells mark a pathogenic T cell-B cell axis in MS
• PD-1 CAR T cells deplete pathogenic CD4 T cells and suppress neuroinflammation
• Inflammation-gated IL-10 delivery locally reprograms the CNS immune niche
To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases.
We found disease-associated enrichment of class-switched immunoglobulin G+(IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features.
To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10.
This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models.
These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.
Web | DOI | Cell | Paywall
Shalita, Rotem; Ben Yehuda, Maya; Gur, Chamutal; Frid, Yasmin; McGrath, Sarah; Suhler, Roni; Bolokan, Lihi; Eisenberg, Vasyl; Eshed, Reut Sharet; Shlomi-Loubaton, Shir; Tofield, Adin; Vardy, Karin; Zada, Mor; Kurilovich, Anna; David, Eyal; Jaitin, Diego; Mazuz, Kfir; Avellino, Roberto; Tzemach, Reut; Kuznetsov, Yuri; Fellus-Alyagor, Liat; Levy-Barda, Adva; Mundt, Sarah; Rosenzweig, Rina; Schreiner, Bettina; Peters, Anneli; Stadelmann, Christine; Zwicky, Pascale; Yarkoni, Adi Wilf; Ingelfinger, Florian; Amit, Ido
Highlights
• Single-cell modeling identifies disease-associated immune circuits in MS CNS tissue• PD-1+ Tfh-like cells mark a pathogenic T cell-B cell axis in MS
• PD-1 CAR T cells deplete pathogenic CD4 T cells and suppress neuroinflammation
• Inflammation-gated IL-10 delivery locally reprograms the CNS immune niche
Summary
B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions.To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases.
We found disease-associated enrichment of class-switched immunoglobulin G+(IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features.
To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10.
This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models.
These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.
Web | DOI | Cell | Paywall
