Chimeric autoantibody receptor T cells clonally eliminate B cells producing autoantibodies against IFN-γ

Neutralizing anti-interferon-γ (IFN-γ) autoantibodies (nAIGAs) impair IFN-γ-mediated immunity, predisposing patients with nAIGAs to infection by nontuberculous mycobacteria, <i>Talaromyces marneffei</i>, and other intracellular pathogens. Current clinical management relies on continuous antimicrobial therapy, with no treatment offering sustained benefits. Here, we developed human chimeric autoantibody receptor (CAAR) T cells targeting autoreactive B cells expressing nAIGA B cell receptors (BCRs) using an IFN-γ receptor-irresponsive IFN-γ variant as bait. By exploiting a mouse model of nAIGA BCR-expressing B cell leukemia, we found that IFN-γ CAAR T cells lack off-target toxicity, including IFN-γ receptor cross-reactive toxicity and Fc-redirected toxicity. IFN-γ CAAR T cells substantially reduced circulating AIGAs secreted from target cells in vivo. Further, IFN-γ CAAR T cells effectively eliminated autoreactive B cells in ex vivo cultures of peripheral blood mononuclear cells from patients with nAIGAs. Together, these results demonstrate that IFN-γ CAAR T cells may be a promising strategy to ameliorate nAIGA-associated infections by eliminating autoreactive B cells.

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Publication Details

Journal
Science Immunology
Published
2025-05-09
DOI
https://doi.org/10.1126/sciimmunol.adm8186
Citations
8
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
8.36
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article

Chimeric autoantibody receptor T cells clonally eliminate B cells producing autoantibodies against IFN-γ

Ling-Shan Syue, Chia-Huei Chou, Wei‐Te Lei, Tsai-Yi Wu et al.
8 citations
Science Immunology
CAR-T cell therapy research
8.36
article

Chimeric autoantibody receptor T cells clonally eliminate B cells producing autoantibodies against IFN-γ

Ling-Shan Syue, Chia-Huei Chou, Wei‐Te Lei, Tsai-Yi Wu, Jing-Ya Ding, Yuag-Meng Liu, Soon-Hian Teh, Yu-Fang Lo, Ping‐Chih Ho, Chen‐Hsiang Lee, Kun‐Hua Tu, Ting‐Shu Wu, Huang-Shen Lin, You-Ning Lin, Shang‐Yu Wang, Yingxi Xu, Jhan-Jie Peng, Cheng‐Chang Yeh, Han-Po Shih, Cheng‐Lung Ku, Yi‐Chun Chen, Po‐Lin Chen, Ya-Ting Chang, Wen‐Chi Huang, Zhi-Yuan Shi, Chia‐Chi Lo, Chen-Yen Kuo, Mao-Wang Ho
article en
8 citations

Abstract

Neutralizing anti-interferon-γ (IFN-γ) autoantibodies (nAIGAs) impair IFN-γ-mediated immunity, predisposing patients with nAIGAs to infection by nontuberculous mycobacteria, <i>Talaromyces marneffei</i>, and other intracellular pathogens. Current clinical management relies on continuous antimicrobial therapy, with no treatment offering sustained benefits. Here, we developed human chimeric autoantibody receptor (CAAR) T cells targeting autoreactive B cells expressing nAIGA B cell receptors (BCRs) using an IFN-γ receptor-irresponsive IFN-γ variant as bait. By exploiting a mouse model of nAIGA BCR-expressing B cell leukemia, we found that IFN-γ CAAR T cells lack off-target toxicity, including IFN-γ receptor cross-reactive toxicity and Fc-redirected toxicity. IFN-γ CAAR T cells substantially reduced circulating AIGAs secreted from target cells in vivo. Further, IFN-γ CAAR T cells effectively eliminated autoreactive B cells in ex vivo cultures of peripheral blood mononuclear cells from patients with nAIGAs. Together, these results demonstrate that IFN-γ CAAR T cells may be a promising strategy to ameliorate nAIGA-associated infections by eliminating autoreactive B cells.

Science ImmunologyVol. 10(107)
Kaohsiung Medical University (TW), Chang Gung University (TW), China Medical University (TW), Kaohsiung Medical University Chung-Ho Memorial Hospital (TW), Mackay Memorial Hospital (TW), Chang Gung Memorial Hospital (TW), Taichung Veterans General Hospital (TW), Kaohsiung Chang Gung Memorial Hospital (TW), Elixiron Immunotherapeutics (Taiwan) (TW), Linkou Chang Gung Memorial Hospital (TW), Ludwig Cancer Research (CH), Hualien Tzu Chi Medical Center (TW), China Medical University Hospital (TW), Chiayi Chang Gung Memorial Hospital (TW), National Cheng Kung University Hospital (TW), Changhua Christian Hospital (TW), University of Lausanne (CH)
Good health and well-being
Openalex Percentile: Top 2%
CAR-T cell therapy research
8.36
DOISourceOpenAlex
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