T–B interactions yield CD3 + B cells and CD20 + T cells with pathogenic features in multiple sclerosis
Classically, B and T cells are differentiated by their mutually exclusive expression of surface markers such as CD3 and CD20, but it is now established that a few percent of T cells in human blood display also CD20. We analyzed CD3 + CD20 + cells in detail by combining single-cell proteogenomics, FACS, and ImageStream. Thereby, we identified CD3 + B cells and found that about 40% of plasmablasts displayed CD3 in both blood and tonsils. In tonsils, where T–B interactions occur, about 80% of follicular helper T (T fh ) cells displayed CD20. In vitro, coactivation of T and B cells induced marker exchange via trogocytosis. We refer to the resulting cells as “masquerading” lymphocytes and analyzed them in multiple sclerosis (MS). CD20 + T cells were markedly enriched in cerebrospinal fluid, exhibited cytotoxic gene signatures, accumulated in perivascular inflammatory cuffs, and showed increased myelin antigen reactivity. Anti-CD20 therapy (ofatumumab) not only depleted masquerading lymphocytes but also prevented their reinduction. Together, we identify CD3 + B cells as footprints of T–B interactions thereby shifting the paradigm of lymphocyte-specific surface markers and implicate masquerading lymphocytes as active contributors to MS immunopathology.
Authors
- Yoann Gilbart
- Philippe Couttet (ORCID: https://orcid.org/0000-0002-5255-6647)
- Julie Boisclair (ORCID: https://orcid.org/0000-0002-3699-5631)
- Arek Kendirli (ORCID: https://orcid.org/0000-0001-6888-9131)
- Rachel Cuttat (ORCID: https://orcid.org/0000-0001-6019-4837)
- Walter Georgescu
- Tania Kümpfel (ORCID: https://orcid.org/0000-0001-7509-5268)
- Magali Jivkov
- Edgar Meinl (ORCID: https://orcid.org/0000-0002-2570-6785)
- Atay Vural (ORCID: https://orcid.org/0000-0003-3222-874X)
- Valérie Dubost
- Selia Baier (ORCID: https://orcid.org/0009-0003-8988-0584)
- Stephan Winklmeier (ORCID: https://orcid.org/0000-0001-8675-0387)
- Ulrike Naumann (ORCID: https://orcid.org/0000-0001-7783-7675)
- Jan Kranich (ORCID: https://orcid.org/0000-0002-9928-4132)
- Eddie A. James (ORCID: https://orcid.org/0000-0002-7217-5729)
- Samantha Ho (ORCID: https://orcid.org/0009-0003-7279-9595)
- José M. Carballido (ORCID: https://orcid.org/0000-0001-8465-0665)
- Eva Oswald (ORCID: https://orcid.org/0009-0004-0888-0978)
- Simone Mader (ORCID: https://orcid.org/0000-0002-2844-9091)
- Selen Ünlü
- Christoph Andreas Reichel (ORCID: https://orcid.org/0000-0003-2145-0388)
- Ceren Özdemir
- Jan M. Schmidt (ORCID: https://orcid.org/0009-0005-8356-4067)
- Nathalie Loll (ORCID: https://orcid.org/0009-0008-6429-3929)
- Fady Shenouda (ORCID: https://orcid.org/0009-0007-3515-0569)
- Zhongyi Wang
Institutions
- Koç University (TR)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Basel (CH)
- International Council on Mining and Metals (GB)
- LMU Klinikum (DE)
- Universitätsklinikum Erlangen (DE)
- Munich Cluster for Systems Neurology (DE)
- Benaroya Research Institute
- Institut für Klinische Neuroimmunologie (DE)
- Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (TR)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-10-01
- DOI
- https://doi.org/10.1073/pnas.2605806123
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00