Biology subjects

Fomin, M.

Publications and source records attributed to Fomin, M..

3 recordsLinked to original sources

bioRxiv2026

Atherosclerosis destabilizes regulatory T cells (Tregs) resulting in multiple families of exTregs

How regulatory T cells (Tregs) lose lineage identity during chronic inflammation remains poorly understood. Here, using inducible Foxp3 lineage tracing together with single-cell transcriptomic, proteomic and T cell receptor (TCR) profiling in atherosclerosis-prone mice, we identify Treg destabilization as a staged and branching differentiation process rather than an abrupt loss of lineage identity. Conventional Tregs (cTregs) first transition through an effector Treg (eTreg) intermediate characterized by attenuation of the CD25-STAT5 axis while retaining core Treg features, before diversifying into eight transcriptionally distinct exTreg states, including Tfh-like, cytotoxic, Th1-like inflammatory, Th1-like cytotoxic and proliferative populations. Trajectory inference, TCR clonotype analysis and experimental Treg-to-exTreg conversion independently converged on this developmental framework, revealing that clonally related exTregs acquire distinct effector programs. Mechanistically, we identify Treg-intrinsic IL-6R signaling as an important driver of this process. IL-6 accelerated exTreg generation in vitro, whereas Treg-specific deletion of Il6ra reduced inflammatory exTreg differentiation and attenuated atherosclerosis in vivo. Together, these findings establish a framework for Treg destabilization during atherosclerosis and provide a conceptual basis for preserving Treg lineage stability in chronic inflammatory disease.

immunology↗

bioRxiv2026

Talin-1 determines the direction of primary mouse neutrophils migrating in vivo

Talin-1 is essential for {beta}2 integrin activation in neutrophils, yet its dynamic behavior during neutrophil trafficking in vivo remains poorly understood. Here, we generated EGFP-talin1 knock-in mice, enabling real-time visualization of talin-1 dynamics under physiological conditions. EGFP-talin1 is robustly expressed and preserves without altering {beta}2 integrin expression and activation. Using total internal reflection fluorescence (TIRF) microscopy under flow, we found that talin-1 was rapidly recruited to the plasma membrane during rolling and accumulates further during neutrophil arrest. Intravital microscopy revealed highly dynamic and stage-specific talin-1 redistribution during luminal crawling, transendothelial migration, and interstitial migration. Talin-1 preferentially accumulated at endothelial contact sites during crawling and polarized toward the leading edge during directional migration. These findings establish EGFP-talin1 knock-in mice as platform for visualizing integrin-associated cytoskeletal dynamics in vivo and identify dynamic talin-1 polarization as a feature of neutrophil trafficking.

immunology↗

bioRxiv2022

Topologically engineered antibodies and Fc-fusion proteins: a new class of multifunctional therapeutic candidates for SARS-CoV-2, cancer, and other disease

Traditional Y-shaped IgG topologies restrict conventional multispecific antibodies by imposing steric constraints that hinder target binding and stability. To overcome this, we engineered tetrahedral antibodies, a multispecific class that non-covalently self-assembles via two hinge-integrated collectrin-like domains (CLDs). This non-planar, tetrapartite architecture coordinates up to six unobstructed Fab, Fc, and extracellular domains. Parallel to the clinical translation of our dual-Fc anti-CD19/CD20 tetrahedral antibody for systemic lupus erythematosus (SLE), we evaluated an anti-SARS-CoV-2 candidate that exhibited in vivo efficacy in non-human primates. Furthermore, we demonstrate functional Fc{gamma}R binding cooperativity across the dual-Fc domains of anti-CD19/CD20 tetrahedral antibodies, while introducing an interface disulfide bond into the CLD dimer increases structural stability as evidenced by effectively abolishing CLD dynamic dissociation and resolving the dissociation equilibrium into discrete, stable quaternary states. These findings establish tetrahedral architectures as a robust, translatable multispecific platform.

molecular biology↗