CD99-mediated immunological synapse formation potentiates CAR-T cell function
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.
Authors
- Eun Mi Hwang (ORCID: https://orcid.org/0000-0002-3130-8572)
- Hyeryeon Jung (ORCID: https://orcid.org/0000-0001-5179-8604)
- Hye Ran Yeon
- Woo-Jeong Shon (ORCID: https://orcid.org/0000-0002-5521-5768)
- Joon‐Yong An (ORCID: https://orcid.org/0000-0001-8839-6297)
- Byoung-Kyu Cho (ORCID: https://orcid.org/0000-0003-3370-6985)
- Hoon Ryu (ORCID: https://orcid.org/0000-0001-6544-3732)
- Eugene C. Yi (ORCID: https://orcid.org/0000-0002-0615-7397)
- Kyungho Choi (ORCID: https://orcid.org/0000-0003-1635-173X)
- Jun Chang (ORCID: https://orcid.org/0000-0002-8423-5987)
- Young-Jae Lee
- Seoyeon Kim (ORCID: https://orcid.org/0000-0001-9184-7087)
- Seoho Lee
- Giri Nam (ORCID: https://orcid.org/0009-0004-6475-1652)
- Eun Young Choi (ORCID: https://orcid.org/0000-0002-2441-3374)
- Ji Hwan Kim (ORCID: https://orcid.org/0000-0002-6488-1068)
- Hyeonji Lim
- Hanna Chang
- Ji Eun Lee
- Hyung Bae Park
Institutions
- Ewha Womans University (KR)
- Seoul National University (KR)
- Cancer Research Institute (US)
- Korea University (KR)
- New Generation University College (ET)
- Korea Pharma (South Korea) (KR)
- Korea Institute of Brain Science (KR)
- National University College (PR)
- Korean Association Of Science and Technology Studies (KR)
- Korea Institute of Science and Technology (KR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-27
- DOI
- https://doi.org/10.1038/s41467-025-63184-w
- Citations
- 2
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- National Research Foundation
- Korea University
- Korea Institute of Science and Technology
- National Research Foundation of Korea
- Korea Drug Development Fund
- Ministry of Science and ICT, South Korea