CD99-mediated immunological synapse formation potentiates CAR-T cell function

Giri Nam, Hye Ran Yeon, Hyung Bae Park, Hanna Chang, Ji Hwan Kim, Byoung-Kyu Cho, Hyeryeon Jung, Eugene C. Yi, Seoyeon Kim, Joon-Yong An, Ji Eun Lee, Youngjae Lee, Seoho Lee, Hyeonji Lim, Woo-Jeong Shon, Eun Mi Hwang, Hoon Ryu, Jun Chang, Kyungho Choi () and Eun Young Choi ()
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Giri Nam: Seoul National University
Hye Ran Yeon: Seoul National University College of Medicine
Hyung Bae Park: Seoul National University
Hanna Chang: Seoul National University
Ji Hwan Kim: Seoul National University
Byoung-Kyu Cho: Seoul National University
Hyeryeon Jung: Seoul National University
Eugene C. Yi: Seoul National University
Seoyeon Kim: Korea University
Joon-Yong An: Korea University
Ji Eun Lee: Seoul National University College of Medicine
Youngjae Lee: Seoul National University
Seoho Lee: Seoul National University
Hyeonji Lim: Seoul National University
Woo-Jeong Shon: Seoul National University College of Medicine
Eun Mi Hwang: Korea Institute of Science and Technology
Hoon Ryu: Korea Institute of Science and Technology
Jun Chang: Ewha Womans University
Kyungho Choi: Seoul National University
Eun Young Choi: Seoul National University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Despite the efficacy of chimeric antigen receptor (CAR)-T cells in selected hematological malignancies, further improvement on CAR-T designs is still desirable. We hypothesize that modifying the CAR structure to enhance immunological synapse (IS) stabilization and CAR target-binding may be a feasible strategy. Here we show that the membrane protein, CD99, is critical for IS formation in T cells by mediating actin-microtubule interaction. CD99 deficiency abolishes IS formation and prevents effective in vivo T cell immunity. Mechanistically, CD99 interacts with microtubules and actins through the transmembrane and cytoplasmic domains, respectively, with which myosin and IQGAP1 interact. As such, incorporating the transmembrane and juxtamembrane domains of CD99 into the CAR structure enhances IS formation and improves the therapeutic efficacy of human CAR-T cells against lymphoma in immune-deficient mice. Our data thus suggest that CD99-mediated IS stabilization may help improve CAR design and efficacy.

Date: 2025
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DOI: 10.1038/s41467-025-63184-w

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