Biology subjects

Patskovsky, Y.

Publications and source records attributed to Patskovsky, Y..

3 recordsLinked to original sources

bioRxiv2026

Autoantibodies Drive Fc Gamma Receptor-Dependent Colon Inflammation During Immune Checkpoint Blockade

Immune checkpoint inhibitor (ICI)-associated colitis limits effective cancer immunotherapy, yet host determinants of severe toxicity remain undefined. We investigated whether humoral immunity is associated with subsequent severe immune-related colitis (irC). In melanoma patients, baseline serum autoantibody (AAb) profiling identified a composite antigen signature - a signature-level association rather than validated functional specificities - associated with severe irC, marked by retained reactivity to tumor-associated antigens and relative depletion of antibodies recognizing immune- and mucosal-regulatory proteins. To assess functional relevance, we transferred polyclonal IgG from severe- or non-severe-irC patients into wild-type or humanized Fc{gamma} receptor (hFc{gamma}R) mice treated with anti-PD-1 or anti-CTLA-4. IgG alone did not induce inflammation; however, severe-irC IgG amplified checkpoint-driven colonic inflammation in hFc{gamma}R mice, but not in wild-type mice, with checkpoint-specific remodeling of myeloid, lymphoid, and innate lymphoid compartments. These findings suggest that pretreatment humoral immunity conditions susceptibility to irC via the IgG-Fc{gamma}R axis.

cancer biology↗

bioRxiv2025

Persistent Classical and Atypical Memory B Cells Underlie Heterogeneous Vaccine Responses in Ocrelizumab-Treated Multiple Sclerosis

Background and ObjectivesPatients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR), a B-cell-depleting therapy, exhibit heterogeneous humoral responses to SARS-CoV-2 mRNA vaccination. The mechanisms underlying this variability remain incompletely understood. We performed a longitudinal analysis of B-cell subset dynamics and antigen-specific T cell responses in OCR-treated pwMS and healthy controls to determine how immune cell composition, timing of OCR infusion, and lymphocyte dynamics influence humoral response outcomes. MethodsBased on post-vaccination anti-Spike IgG titers measured by multiplex bead immunoassay, pwMS were categorized as super-responders (SR), responders (R), or non-responders (NR). A 35-marker spectral flow cytometry panel was used to characterize T- and B-cell subsets longitudinally, at baseline and following stimulation with a SARS-CoV-2 peptide pool. ResultsCD4+ and CD8+ T cell populations were preserved across OCR-treated pwMS, and SARS-CoV-2-specific T cells remained detectable for more than 6 months after vaccination. In contrast, residual B-cell subset composition distinguished responders from non-responders. DN2-like B cells (CD19+CD27-IgD-T-bet+CD11c+CXCR5-) persisted despite repeated OCR infusions and were enriched in SR compared with NR. Repletion of mature naive B cells in peripheral blood correlated with time since last OCR infusion and with stronger humoral immune responses. ConclusionsB-cell subsets that resist OCR-mediated depletion may contribute to vaccine responsiveness in OCR-treated pwMS. Altered repletion kinetics of naive B cell subsets in non-responders suggest that specific B-cell populations may serve as predictive biomarkers of vaccine-induced humoral immunity, despite preserved T-cell responses.

immunology↗

bioRxiv2025

FGL-1 binding to LAG-3 inhibits T cell activation via disruption of CD28 and TCR signaling

Lymphocyte-activation gene 3 (LAG-3) is known to suppress T cell receptor (TCR) signaling by disrupting CD4/CD8 coreceptor and Lck association in the absence of ligand binding. However, the impact of Fibrinogen-like protein 1 (FGL-1) binding in modulating LAG-3 mediated inhibition and its specific impact on CD28 costimulatory signaling remains unclear. This study investigates the role of LAG-3/FGL-1 interaction in modulating T cell activation. Using phosphoproteomics and confocal microscopy in LAG-3+ Jurkat cells, we demonstrated that LAG-3/FGL-1 interaction suppresses T cell activation by disrupting CD28-mediated recruitment of Lck, impairing its colocalization with CD28. Importantly, this inhibition occurs independently of CD4-bound Lck, indicating that LAG-3 ligand engagement targets both free and membrane-associated Lck pools. Consequently, this leads to suppressed phosphorylation of CD28 and TCR/CD3 signaling components, broadly attenuating downstream tyrosine phosphorylation and T cell effector functions. Our findings identify the CD28-Lck axis as a critical target of LAG-3/FGL-1 inhibitory pathway and provide a rationale for therapeutic strategies that reinvigorate CD28-Lck signaling to enhance anti-tumor immunity.

immunology↗