Biology subjects

Larson, J. H.

Publications and source records attributed to Larson, J. H..

3 recordsLinked to original sources

bioRxiv2026

Human CD8-iTreg are potent GVHD suppressors and tumoricidal effectors by release of Granzyme-K+ Supramolecular Attack Particles

Regulatory CD8+ T-cells (CD8+ Treg) are a distinct yet understudied T-cell subset capable of simultaneous immunosuppression and cytolysis. Here, we characterized induced human CD8+ Treg (CD8-iTreg) generated from peripheral blood CD8+CD25- T-cells using anti-CD3e mAb-loaded artificial antigen presenting cells, IL-2, TGF{beta}, and Rapamycin. These CD8-iTreg differentiated into a stable, highly proliferative bifunctional population with suppressive activity comparable to CD4-iTreg while retaining cytolytic capacity similar to conventional CD8 cytotoxic T lymphocytes (CTL). Multi-parameter spectral flow cytometry and single-cell RNA-seq revealed a distinct immunoregulatory signature: a predominantly Treg-like profile marked by tissue-residency marker CD103 with increased canonical Treg markers (FoxP3, HELIOS, CD25, CD39, CTLA-4, CCR4, and IL-10) and reduced pro-inflammatory cytokines. A unique cytotoxic program was marked by elevated Granzyme-K (GzmK) and Thrombospondin-4 (Tsp-4), a thrombospondin family extracellular matrix glycoprotein upregulated in activated CD8+ T-cells. Cytolysis was primarily mediated by Perforin (Prf) and multiple Granzymes packaged into Tsp-4 supramolecular attack particles (SMAPs), with GzmK contributing to both cytotoxic and suppressive functions. After anti-CD19scFv CAR (CAR19) transduction, CAR19+ CD8-iTreg showed superior in vivo anti-tumor efficacy compared with CAR19-CTLs, significantly reducing tumor burden and prolonging survival in a CD19+ Nalm-6 human leukemia xenograft model while maintaining low pro-inflammatory cytokine production. In a xenogeneic graft-versus-host disease (GVHD) model with residual human leukemia, CAR19 CD8-iTreg inhibited GVHD lethality and controlled tumor growth without increasing systemic inflammation. Together, these findings support CD8-iTreg-based CAR therapies as a strategy to retain potent anti-leukemic activity while limiting inflammatory toxicities of conventional CAR T-cells, properties particularly beneficial in treating auto- and allo-immune diseases. One sentence summaryCD8-iTreg drive parallel tumoricidal and immunoregulatory functions mediated by releasing Tsp-4+ SMAPs containing granzyme K.

immunology↗

bioRxiv2024

Effect of copper mill waste material on benthic invertebrates and zooplankton diversity and abundance in Lake Superior beaches

From 1900 to 1932 a copper (Cu) mill operated near Gay, Michigan, along the eastern shore of the Keweenaw Peninsula (Lake Superior, Michigan) and discharged waste material (stamp sands [SS]) to a nearby beach. These SS escaped containment structures and have been redeposited by wave action along the beaches in northern Grand Traverse Bay and onto Buffalo Reef, an important spawning area for native fish. Newly hatched fish move into nearby beach habitats where they grow during their first summer. Juvenile fish initially consume zooplankton before switching to benthic invertebrates once they are large enough. SS contain metals (especially Cu) that are toxic to many invertebrate taxa, and studies have observed few benthic taxa in areas covered by SS. We sampled the invertebrate community from four Lake Whitefish nursery areas: one near Buffalo Reef with high SS, one south of the Traverse River with moderate SS, one in nearby Little Traverse Bay with little SS, and a beach [~]58 km away with no SS (Big Bay). We also resampled the benthos at sites that had been sampled as part of an earlier Grand Traverse Bay study. Buffalo Reef (high SS) had fewer benthic taxa, and less density of several taxa than Little Traverse Bay (little SS), especially benthic copepods. All beaches had comparable zooplankton diversity, but the abundance was [~]2 orders of magnitude lower at Buffalo Reef (high SS) than other beaches. Cu and several other metals were elevated at beaches with more SS. We found support for associations between benthic density and diversity with depth (positive effect) and Cu concentration (negative effect). Cu concentration was a better predictor of declines in benthic invertebrate abundance and diversity than SS. We also observed that the relationship between Cu concentration and SS was non-linear, and highly variable. For example, 149 mg Cu/kg dry weight sediment is a consensus toxicity threshold used in the literature, but the prediction interval around that concentration from our model is 26-851 mg Cu/kg dry weight. A better predictive model of this relationship would be beneficial to develop to understand what level of SS reduction would prevent Cu impacts on invertebrates.

ecology↗

bioRxiv2017

Mercury and water level fluctuations in lakes of northern Minnesota

Large lake ecosystems support a variety of ecosystem services in surrounding communities, including recreational and commercial fishing. However, many northern temperate fisheries are contaminated by mercury. Annual variation in mercury accumulation in fish has previously been linked to water level (WL) fluctuations, opening the possibility of regulating water levels in a manner that minimizes or reduces mercury contamination in fisheries. Here, we compiled a long-term dataset (1997-2015) of mercury content in young-of-year Yellow Perch (Perca flavescens) from six lakes on the border between the U.S. and Canada and examined whether mercury content appeared to be related to several metrics of WL fluctuation (e.g., spring WL rise, annual maximum WL, and year-to-year change in maximum WL). Using simple correlation analysis, several WL metrics appear to be strongly correlated to Yellow Perch mercury content, although the strength of these correlations varies by lake. We also used many WL metrics, water quality measurements, temperature and annual deposition data to build predictive models using partial least squared regression (PLSR) analysis for each lake. These PLSR models showed some variation among lakes, but also supported strong associations between WL fluctuations and annual variation in Yellow Perch mercury content. The study lakes underwent a modest change in WL management in 2000, when winter WL minimums were increased by about 1 m in five of the six study lakes. Using the PLSR models, we estimated how this change in WL management would have affected Yellow Perch mercury content. For four of the study lakes, the change in WL management that occurred in 2000 likely reduced Yellow Perch mercury content, relative to the previous WL management regime.

ecology↗