Koseoglu, M. | Search bioRxiv

bioRxiv2026

CD8+CD20+ Cytotoxic T Lymphocytes Exhibit Augmented Degranulation and Pro-inflammatory Potential in Multiple Sclerosis

The effectiveness of CD20-targeting therapies in multiple sclerosis (MS) underscores the role of B cells in the disease, yet the limited success of other B cell-specific treatments suggests additional mechanisms at play. Intriguingly, CD20 is also expressed on a subset of highly active memory T cells, particularly cytotoxic CD8+ T lymphocytes (CTLs). This study investigated the functional characteristics of CD8+CD20+ CTLs in MS. We observed a significant increase in CD8+CD20+ CTL prevalence in MS patients, with enhanced infiltration into the cerebrospinal fluid. Consistent with prior reports, these cells exhibited heightened proliferation and production of IFN-{gamma}, TNF-, and GM-CSF. Notably, we demonstrate for the first time that CD8+CD20+ CTLs display escalated degranulation and produce significantly higher levels of Granzyme B, Perforin, and Granzyme K compared to their CD20-counterparts, with further augmentation in pwMS compared to healthy controls. These findings suggest that in MS, CD8+CD20+ CTLs are actively recruited to the CNS, exhibiting enhanced cytotoxicity and a potent pro-inflammatory profile, particularly through elevated Granzyme K production, contributing significantly to the chronic inflammatory milieu and immunopathogenesis of MS.

immunology↗

bioRxiv2025

CD20+ natural killer cells are polyfunctional, memory-like cells that are enriched in inflammatory disorders

While CD20 was initially characterized as a B cell-specific marker, its expression on memory T cells has expanded our understanding of this molecules distribution and function. Here, we identify a previously unrecognized CD20-expressing NK cell population and demonstrate its functional significance. CD56+CD20+ NK cells exhibit hallmarks of cellular activation, including elevated NKp46, CD69, and CD137 expression, enhanced proliferative capacity, and increased production of inflammatory cytokines (IFN-{gamma}, GM-CSF, TNF-, IL-10). Functional analyses revealed enhanced cytotoxicity against K562 targets, correlating with increased expression of cytolytic mediators including granzymes A, B, and K, perforin, FASL, and TRAIL. Single-cell transcriptional profiling demonstrated that MS4A1-expressing NK cells possess a distinct molecular signature characterized by elevated granzyme K expression and memory-like features. These cells preferentially localize to secondary lymphoid organs and accumulate in inflammatory tissues. Notably, CD56+CD20+ NK cells are enriched in multiple inflammatory conditions, including multiple sclerosis, autoimmune hepatitis, hepatitis B infection, hepatocellular carcinoma, and lung cancer. Treatment with rituximab depletes this population, suggesting potential therapeutic implications. Our findings establish CD20+ NK cells as a functionally distinct lymphocyte subset with enhanced effector capabilities and tissue-homing properties, providing new insights into immune regulation in inflammatory diseases. One Sentence SummaryOur study reveals expression of CD20 by NK cells, in relation with enhanced functionality, memory-like features, and inflammation.

immunology↗