Biology subjects

Tu, S.-M.

Publications and source records attributed to Tu, S.-M..

4 recordsLinked to original sources

bioRxiv2026

Interferon-γ promotes SMAP production by cytotoxic T lymphocytes in a thrombospondin 4 dependent manner

Cytotoxic T lymphocytes (CTLs) eliminate infected and cancerous cells by exocytosing cytotoxic granules, either as single-core granules (SCGs) releasing diffusible Granzyme B and Perforin, or as multi-core granules (MCGs) releasing these effectors as thrombospondin-1/4-encapsulated supramolecular attack particles (SMAPs). How CTLs differentially deploy these granule types remains unclear. We demonstrate that prolonged in vitro expansion and restimulation selectively enhance SMAP release, correlating with increased MCG maturation and thrombospondin-4 expression. Using high-resolution imaging, we identify fusion-competent MCG intermediates lacking SMAPs but releasing granzyme B diffusively. Mechanistically, interferon-{gamma} upregulates thrombospondin-4, driving MCG maturation and SMAP biogenesis, enhancing late-phase CTL killing efficiency against resistant targets. Consistent with this, THBS1 and THBS4 transcript levels appear elevated in melanoma-infiltrating CTLs compared with those during acute adenovirus infection. These findings define a stimulus-dependent, interferon-{gamma}-driven pathway tailoring CTL responses to chronic pathology and highlight opportunities for SMAP-targeted immunotherapies.

immunology↗

bioRxiv2025

Distinct Flower signaling domains orchestrate cellular fitness via secreted vesicles in Aβ-induced neurodegeneration

Cellular fitness surveillance preserves tissue integrity, yet its regulation within the mammalian brain remains poorly understood. We identify a bifurcated mechanism in the transmembrane protein Flower--encoding both survival-promoting ("win") and apoptosis-inducing ("lose") isoforms. We demonstrate that astrocytes secrete specialized extracellular vesicles (EVs), termed "fitness vesicles," carrying Flower to facilitate competitive selection across distal cell populations. The N-terminal Flower domain acts extrinsically via these EVs to drive the elimination of less-fit neighbors. Conversely, the "win"-specific C-terminal domain functions as a cell-intrinsic module; it translocates to the nucleus under stress to repress Caspase-3 and provide resilience. In Alzheimers disease (AD) models and human AD brains, Flower-positive astrocytes accumulate around amyloid-{beta} (A{beta}) plaques. Under A{beta} stress, the "win" isoform reprograms astrocytes toward a neuroprotective state that enhances plaque clearance while ensuring cell-intrinsic survival. Our findings reveal how Flower couples long-range, EV-mediated cellular selection with cell-autonomous protection to coordinate astrocyte quality control and tissue resilience in neurodegeneration.

neuroscience↗

bioRxiv2025

Lytic IFNγ is stored in granzyme B-containing cytotoxic granules and co-secreted by effector CD8⁺ T cells

Cytotoxic CD8 T cells form immunological synapses with target cells and release effector molecules, including IFN{gamma}, to mediate antitumor immunity. However, the mechanisms by which IFN{gamma} contributes to cytotoxicity remain incompletely understood. Here, we identify a subset of IFN{gamma} stored within GzmB cytotoxic granules (CGs) in activated mouse and human CD8 T cells, termed lytic IFN{gamma}. Lytic IFN{gamma} is polarized to the synapse and co-secreted with GzmB in both soluble and supramolecular attack particle (SMAP)-associated forms. Mouse CD8 T cells lacking the vesicle priming factor Munc13-4 exhibit impaired both CG and early IFN{gamma} release at the immunological synapse, while prolonged synaptic engagement restores IFN{gamma} secretion. Super-resolution imaging demonstrates that sustained synaptic interactions drive IFN{gamma} secretion at distal membrane sites, suggesting the existence of distinct IFN{gamma} populations with potentially diverse functions beyond lytic IFN{gamma}. These findings uncover an unrecognized mechanism of IFN{gamma} storage and release, underscoring its pivotal role in CD8 T cell-mediated tumor elimination.

immunology↗

bioRxiv2024

Thrombospondins 1 and 4 undergo coordinated transport to multicore cytotoxic granules to regulate SMAP biogenesis and function in CTL-mediatedcytotoxicity

Supramolecular Attack Particles (SMAPs) are particulate entities, characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a glycoproteic shell, released by CTLs and NK cells. Prior proteomic analysis identified thrombospondin-1 (TSP-1) and thrombospondin-4 (TSP-4) as putative components of SMAPs. While TSP-1 has been validated as a component of the SMAP shell and shown to contribute significantly to CTL-mediated killing, the expression and function of TSP-4 in CTLs, and its interplay with TSP-1 in SMAP biogenesis and function, has not been investigated as yet. Here we demonstrate that TSP-4 and TSP-1 have a complementary expression profile during in vitro human CD8+ T cell differentiation to CTLs and sequentially localize to lytic granules (LG), with TSP-4 being required for TSP-1 association with LGs. Correlative light microscopy identified the TSP-enriched LGs as the SMAP-containing multicore granules. We show by STED microscopy a heterogeneity among TSP-enriched LGs, the most abundant population being positive for both TSP-4 and TSP-1. We also show that TSP-1 and TSP-4 are co-released in association with SMAPs at immune synapses formed on planar supported lipid bilayers, as assessed by dSTORM imaging. Finally, we provide evidence that TSP-4 is required for CTL- and SMAP-mediated cell killing. Of note, we found that chronic lymphocytic leukemia (CLL) cell supernatants, which suppress CTL mediated killing, also suppress expression of TSP-4 as well as of cytolytic effectors and impair SMAP biogenesis. These results identify TSP-4 as a key player in SMAP structure and activity and suggest that SMAPs may be a new target for immune suppression by CLL.

immunology↗