Localized PD-1 CAR T therapy reprograms neuroinflammation

Rotem Shalita; Maya Ben Yehuda; Chamutal Gur; Yasmin Frid; Sarah McGrath; Roni Suhler; Lihi Bolokan; Vasyl Eisenberg; Reut Sharet Eshed; Shir Shlomi-Loubaton; Adin Tofield; Karin Vardy; Mor Zada; Anna Kurilovich; Eyal David; Diego Jaitin; Kfir Mazuz; Roberto Avellino; Reut Tzemach; Yuri Kuznetsov; Liat Fellus-Alyagor; Adva Levy-Barda; Sarah Mundt; Rina Rosenzweig; Bettina Schreiner; Anneli Peters; Christine Stadelmann; Pascale Zwicky; Adi Wilf Yarkoni; Florian Ingelfinger; Ido Amit

doi:10.1016/j.cell.2026.06.036

Localized PD-1 CAR T therapy reprograms neuroinflammation

Rotem Shalita
, Maya Ben Yehuda
, Chamutal Gur
, Yasmin Frid
, Sarah McGrath
, Roni Suhler
, Lihi Bolokan
, Vasyl Eisenberg
, Reut Sharet Eshed
, Shir Shlomi-Loubaton
, Adin Tofield
, Karin Vardy
, Mor Zada
, Anna Kurilovich
, Eyal David
, Diego Jaitin
, Kfir Mazuz
, Roberto Avellino
, Reut Tzemach
, Yuri Kuznetsov

Liat Fellus-Alyagor, Adva Levy-Barda, Sarah Mundt, Rina Rosenzweig, Bettina Schreiner, Anneli Peters, Christine Stadelmann, Pascale Zwicky, Adi Wilf Yarkoni, Florian Ingelfinger^*, Ido Amit^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	5743-5765.e10
Journal	Cell
Volume	189
Issue number	18
DOIs	https://doi.org/10.1016/j.cell.2026.06.036
Publication status	Published Online - 21 Jul 2026

Funding

Ms. Tal Bigdary contributed to the visuals. I.A. is an Eden and Steven Romick Professorial Chair, supported by the HHMI International Scholar Award. I.A. is supported by the European Research Council (TROJAN-Cell 101055341 and iCARUS 101292945); the European Union IMMEDIATE program (101095540); the MBZUAI/WIS AI program; the Lotte and John Hecht Memorial Foundation; the Schwartz Reisman Collaborative Science Program; Israel Science Foundation grants (1944/22 and MAPATZ 3447/25); Deutsche Forschungsgemeinschaft (DFG) TRR167 (project ID 259373024); the Israel Cancer Research Fund Research Professorship; BSF; the Israeli Ministry of Innovation, Science, and Technology (1001703362); NIH/NIA (R61AG090394); the Elsie and Marvin Dekelboum Family Foundation; the Alzheimer’s Association (ABA-25-1373817); the Mark Foundation ASPIRE Award; and Gladys Monroy and Larry Marks Center for Research on Brain Disorders. This work was supported by the Morris Kahn Institute for Human Immunology, the Fabrikant-Morse Families Research Fund for Humanity, the Quinquin Foundation, and, at the Weizmann Institute of Science, the Center for Immunotherapy and the AI Hub at the Institute for AI. R. Shalita was supported by NeuroMac School (CRC/TRR167), Azrieli Institute for Brain and Neural Sciences, and the National Bioinnovators Forum (Teva Pharmaceuticals). S. McGrath was supported by the Walter Benjamin programme of the DFG (568898367). C.S. was supported by a DFG individual research grant (STA1389/5-1 and 435430032), the DFG Priority Program (500301720 and STA1389/7-1/2), the DFG under Germany’s Excellence Strategy (EXC2067/1-390729940), the Hertie Foundation, and the National MS Society (USA). P.Z. was supported by the Azrieli International Postdoctoral Fellowship, the Koshland Award, and the Novartis Foundation for Medical-Biological Research Fellowship. F.I. was supported by the Koshland prize and an EMBO postdoctoral fellowship (ALTF 723-2022). F.I. is the recipient of an MSCA postdoctoral fellowship (101106452; STIC-GBM). F.I. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SFB-1479 – project ID: 441891347-P23.

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.cell.2026.06.036

Cite this

Shalita, R., Ben Yehuda, M., Gur, C., Frid, Y., McGrath, S., Suhler, R., Bolokan, L., Eisenberg, V., Eshed, R. S., Shlomi-Loubaton, S., Tofield, A., Vardy, K., Zada, M., Kurilovich, A., David, E., Jaitin, D., Mazuz, K., Avellino, R., Tzemach, R., ... Amit, I. (2026). Localized PD-1 CAR T therapy reprograms neuroinflammation. Cell, 189(18), 5743-5765.e10. Advance online publication. https://doi.org/10.1016/j.cell.2026.06.036

@article{93f9481f1b614f399d234cea38fe892a,

title = "Localized PD-1 CAR T therapy reprograms neuroinflammation",

abstract = "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.",

author = "Rotem Shalita and \{Ben Yehuda\}, Maya and Chamutal Gur and Yasmin Frid and Sarah McGrath and Roni Suhler and Lihi Bolokan and Vasyl Eisenberg and Eshed, \{Reut Sharet\} and Shir Shlomi-Loubaton and Adin Tofield and Karin Vardy and Mor Zada and Anna Kurilovich and Eyal David and Diego Jaitin and Kfir Mazuz and Roberto Avellino and Reut Tzemach and Yuri Kuznetsov and Liat Fellus-Alyagor and Adva Levy-Barda and Sarah Mundt and Rina Rosenzweig and Bettina Schreiner and Anneli Peters and Christine Stadelmann and Pascale Zwicky and Yarkoni, \{Adi Wilf\} and Florian Ingelfinger and Ido Amit",

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Shalita, R , Ben Yehuda, M, Gur, C, Frid, Y, McGrath, S, Suhler, R , Bolokan, L , Eisenberg, V, Eshed, RS, Shlomi-Loubaton, S , Tofield, A , Vardy, K , Zada, M, Kurilovich, A, David, E , Jaitin, D, Mazuz, K, Avellino, R, Tzemach, R , Kuznetsov, Y , Fellus-Alyagor, L, Levy-Barda, A, Mundt, S, Rosenzweig, R, Schreiner, B, Peters, A, Stadelmann, C, Zwicky, P, Yarkoni, AW, Ingelfinger, F & Amit, I 2026, 'Localized PD-1 CAR T therapy reprograms neuroinflammation', Cell, vol. 189, no. 18, pp. 5743-5765.e10. https://doi.org/10.1016/j.cell.2026.06.036

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AU - Shalita, Rotem

AU - Ben Yehuda, Maya

AU - Gur, Chamutal

AU - Frid, Yasmin

AU - McGrath, Sarah

AU - Suhler, Roni

AU - Bolokan, Lihi

AU - Eisenberg, Vasyl

AU - Eshed, Reut Sharet

AU - Shlomi-Loubaton, Shir

AU - Tofield, Adin

AU - Vardy, Karin

AU - Zada, Mor

AU - Kurilovich, Anna

AU - David, Eyal

AU - Jaitin, Diego

AU - Mazuz, Kfir

AU - Avellino, Roberto

AU - Tzemach, Reut

AU - Kuznetsov, Yuri

AU - Fellus-Alyagor, Liat

AU - Levy-Barda, Adva

AU - Mundt, Sarah

AU - Rosenzweig, Rina

AU - Schreiner, Bettina

AU - Peters, Anneli

AU - Stadelmann, Christine

AU - Zwicky, Pascale

AU - Yarkoni, Adi Wilf

AU - Ingelfinger, Florian

AU - Amit, Ido

PY - 2026/7/21

Y1 - 2026/7/21

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105044807540

U2 - 10.1016/j.cell.2026.06.036

DO - 10.1016/j.cell.2026.06.036

M3 - Article

AN - SCOPUS:105044807540

SN - 0092-8674

VL - 189

SP - 5743-5765.e10

JO - Cell

JF - Cell

IS - 18

ER -

Localized PD-1 CAR T therapy reprograms neuroinflammation

Abstract

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