Biology subjects

Akkaya, N.

Publications and source records attributed to Akkaya, N..

4 recordsLinked to original sources

bioRxiv2026

Glucose-Responsive CD20+ Cytotoxic T Cells: A Novel Pro-inflammatory Mediator in the Immunopathogenesis of Type 2 Diabetes

ObjectiveAlthough T-cell-mediated inflammation is a hallmark of Type 2 Diabetes (T2D), the contribution of CD20-expressing T cells--a highly potent subset recently implicated in various autoimmune conditions--to T2D pathogenesis remains unknown. This study aimed to characterize the frequency, functional profile, and glucose-responsiveness of CD20+ cytotoxic T lymphocytes (CTLs) in patients with T2D. Research Design and MethodsPeripheral blood mononuclear cells (PBMCs) from 25 treatment-naive T2D patients and 20 age-matched healthy controls (HC) were analyzed using multicolor flow cytometry. We assessed the frequency of CD3+CD8+CD20+ cells and their production of cytotoxic molecules (Granzyme B, Perforin, Granzyme K) and pro-inflammatory cytokines (IFN-{gamma}, TNF-, GM-CSF). To further establish the link with hyperglycemia, HC-derived CTLs were exposed to increasing glucose concentrations (100-450 mg/dL) in vitro. Single-cell RNA sequencing (scRNA-seq) data from a public T2D dataset was utilized to validate the molecular signature of MS4A1 (CD20)+ CTLs. ResultsThe frequency of circulating CD20+ CTLs was significantly elevated in T2D patients compared to HCs (p<0.0001) and demonstrated a strong positive correlation with HbA1c, fasting glucose, and triglyceride levels. Notably, CD20+ CTLs from T2D patients exhibited a "hyperfunctional" phenotype, characterized by significantly higher degranulation (CD107a), elevated expression of Granzymes B/K and Perforin, and increased production of IFN-{gamma} and TNF- compared to HCs (p<0.01 for all). In contrast, no such differences were observed in the CD20-CTL compartment. In vitro experiments revealed that escalating glucose levels directly enhanced the proliferation and cytotoxic potential of CD20+ CTLs, suggesting a nutrient-sensing mechanism. scRNA-seq analysis further confirmed the distinct pro-inflammatory and effector transcriptional profile of MS4A1+ T cells in T2D. ConclusionsOur findings identify CD20+ CTLs as a novel, glucose-sensitive, and hyperfunctional immune subset in T2D. The strong correlation between these cells and clinical metabolic parameters suggests that CD20+ CTLs may act as a critical link between chronic hyperglycemia and systemic inflammation, representing a potential new therapeutic target for immunomodulation in T2D.

immunology↗

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

Reactive Pericytes Lead to Microvascular Dysfunction and Cortical Neurodegeneration During Experimental Autoimmune Encephalomyelitis

The mechanisms underlying neurodegeneration in multiple sclerosis remain incompletely understood. In this study, we aimed to investigate the role of vascular dysfunction in cortical neurodegeneration using a chronic cranial window model of experimental autoimmune encephalomyelitis in mice. After the induction of experimental autoimmune encephalomyelitis with myelin oligodendrocyte glycoprotein peptides in C57BL/6J mice, we assessed cerebrovascular reactivity though a chronic cranial window using laser speckle contrast imaging and intrinsic optical signal imaging in awake animals. We observed a significant reduction in cortical cerebrovascular reactivity during peak inflammation in the EAE group, as detected by laser speckle contrast imaging after 5% hypercapnia (p=0.04) and optical signal imaging after whisker stimulation (p=0.008). Histological analysis revealed a diffuse increase in CD13+ pericyte coverage (p=0.001), accompanied by focal IgG deposition within the microvascular lumen (p=0.04) and increased amount of CD45+ leukocytes stalled in microvessels (p=0.03) in the cortex of experimental autoimmune encephalomyelitis mice. Microglial activation was also present in the cortex of experimental autoimmune encephalomyelitis mice (p=0.04) and was particularly evident around microvessels with IgG deposition. Subpial and intracortical foci exhibiting loss of NeuN reactivity (p=0.03) and axonal loss (p=0.007) were detected in experimental autoimmune encephalomyelitis, but not in control mice. Altogether, these results demonstrate that microvascular function and neurovascular unit elements are globally affected in the cortex during autoimmune neuroinflammation and is related to neurodegeneration.

neuroscience↗

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↗