Biology subjects

Temu, T.

Publications and source records attributed to Temu, T..

4 recordsLinked to original sources

bioRxiv2025

Characterization of Distinct Monocyte Subtypes and Immune Features Associated with HIV, Tuberculosis, and Coronary Artery Disease in a Ugandan Cohort Using Mass Cytometry

Coronary artery disease (CAD), tuberculosis (TB), and HIV represent major global health burdens. Individuals affected by one or more of these conditions often exhibit chronic inflammation and immune dysregulation, with monocytes playing a central role in these processes. Monocyte subsets are known to expand in individuals with HIV, TB, or CAD. However, the precise mechanisms by which these cells contribute to inflammation and immune responses in the context of these conditions remain poorly understood. In this study, we employed high-dimensional mass cytometry to characterize monocyte heterogeneity in 61 Ugandan adults with varying combinations of HIV, latent TB, and subclinical or overt CAD. Through an integrative approach combining manual gating, unsupervised clustering, and elastic net penalization, we identified distinct monocyte phenotypes associated with CAD and TB. Importantly, individuals with CAD, especially those with more extensive disease (Segment Involvement Score >2), showed reduced surface expression of the anti-inflammatory scavenger receptor CD163 on non-classical monocytes. Notably, unsupervised clustering further revealed two distinct non-classical monocyte subsets associated with disease states: A CD86dim CX3CR1dim CD45RA+ GPR56+ CXCR3+ subset significantly depleted in individuals with CAD, and a CD86+ CX3CR1++ CD45RA++ GPR56- CD38- CXCR3- subset enriched in individuals with TB. These findings underscore the complexity of the monocyte landscape in CAD progression, particularly within settings of HIV and TB co-endemicity. We hope this work motivates further research and offers insights for the development of new precision biomarkers and immune-targeted therapies to prevent or treat CAD, TB, and HIV in populations.

bioinformatics↗

bioRxiv2024

Cytokine and Chemokine Receptor Profiles in Adipose Tissue Vasculature Unravel Endothelial Cell Responses in HIV

Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation. We first broadly phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in adipose tissue in the subcutaneous adipose tissue of 59 PLWH using single cell transcriptomic analysis. We used CellChat to predict cell-cell interactions between ECs and other cells in the adipose tissue and Spearman correlation to measure the association between ECs and plasma cytokines. Finally, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk sequencing to study the direct effects ex-vivo. We observed that arterial and capillary ECs expressed higher interferon and tumor necrosis factor (TNF) receptors. Venous ECs had more interleukin (IL)-1R1 and ACKR1 receptors, and VSMCs had high significant IL-6R expression. CellChat predicted ligand-receptor interactions between adipose tissue immune cells as senders and capillary ECs as recipients in TNF-TNFRSF1A/B interactions. Chemokines expressed largely by capillary ECs were predicted to bind ACKR1 receptors on venous ECs. Beyond the adipose tissue, the proportion of venous ECs and VSMCs were positively plasma IL-6. In ex-vivo experiments, HAECs cultured with plasma-conditioned media from PLWH expressed transcripts that enriched for the TNF- and reactive oxidative phosphorylation pathways. In conclusion, ECs demonstrate heterogeneity in cytokine and chemokine receptor expression. Further research is needed to fully elucidate the role of cytokines and chemokines in EC dysfunction and to develop effective therapeutic strategies.

cell biology↗

bioRxiv2023

Distinct blood CD3+ CD14+ T Cell-Monocyte complexes harbor HIV and are dynamic, glucose-dependent, and increased in individuals with glucose intolerance

An increased risk of cardiometabolic disease accompanies persistent systemic inflammation. Yet, the innate and adaptive immune system features in persons who develop these conditions remain poorly defined. Doublets, or cell-cell complexes, are routinely eliminated from flow cytometric and other immune phenotyping analyses, which limits our understanding of their relationship to disease states. Using well-characterized clinical cohorts, including participants with controlled HIV as a model for chronic inflammation and increased immune cell interactions, we show that circulating CD14+ monocytes complexed to CD3+ T cells are dynamic, biologically relevant, and increased in individuals with diabetes after adjusting for confounding factors. The complexes form functional immune synapses with increased expression of proinflammatory cytokines and greater glucose utilization. Furthermore, in persons with HIV, the CD3+T-cell: CD14+monocyte complexes had more HIV copies compared to matched CD14+ monocytes or CD4+ T cells alone. Our results demonstrate that circulating CD3+T-cell:CD14+monocyte pairs represent dynamic cellular interactions that may contribute to inflammation and cardiometabolic disease pathogenesis and may originate or be maintained, in part, by chronic viral infections. These findings provide a foundation for future studies investigating mechanisms linking T cell-monocyte cell-cell complexes to developing immune-mediated diseases, including HIV and diabetes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/538020v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@fdc324org.highwire.dtl.DTLVardef@168fc4org.highwire.dtl.DTLVardef@138a9a0org.highwire.dtl.DTLVardef@1087108_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICirculating CD3+ CD14+ T cell-monocyte complexes are higher in individuals with diabetes. C_LIO_LICD3+ CD14+ T cell-monocytes complexes comprise a heterogenous group of functional and dynamic cell-cell interactions. C_LIO_LIThe proportion of CD3+ CD14+ T cell-monocyte complexes is positively associated with fasting blood glucose and negatively with plasma IL-10 levels and CD4+ T regulatory cells. C_LIO_LICD3+ CD14+ T cell-monocyte complexes are metabolically flexible and can utilize both glycolysis and oxidative phosphorylation for their energy requirements. C_LIO_LIIn persons with treated HIV, CD3+ CD14+ T cell-monocytes have more detectable HIV DNA than circulating CD4+ T cells alone. C_LI

immunology↗

bioRxiv2020

Digital spatial profiling of coronary plaques from persons living with HIV reveals high levels of STING and CD163 in macrophage enriched regions

BackgroundChronic innate and adaptive immune activation may contribute to high prevalence of cardiovascular disease in persons living with HIV (PLWH). MethodsWe assessed coronary plaques from deceased PLWH (n=6) and HIV-negative (n=6) persons matched by age and gender. Formalin-fixed, paraffin-embedded 5m thick sections were processed using Movat, hematoxylin and eosin, immunohistochemical and immunofluorescence stains. Immune cell populations were measured using surface antibodies, and immune-related protein expression from macrophage rich, T-cell rich and perivascular adipose tissue regions using GeoMx(R) digital spatial profiling. ResultsCoronary plaques from PLWH and HIV-negative persons had similar plaque area and percent stenosis. Percent CD163+ cells as measured by immunohistochemical staining was significantly higher in PLWH, median 0.29% (IQR 0.11-0.90) vs. 0.01% (IQR 0.0013-0.11) in HIV-negative plaque, p = 0.02 (Figure 1A). Other surface markers of innate cells (CD68 +, p=0.18), adaptive immune cells (CD3+, p=0.39; CD4+, p=0.09; CD8+, p=0.18) and immune trafficking markers (CX3CR1+, p=0.09) within the coronary plaque trended higher in HIV-positive plaques but did not reach statistical significance. GeoMx(R) digital spatial profiling showed higher differential protein expression of CD163 (scavenger receptor for hemoglobin-haptoglobin complex), stimulator of interferon gamma (STING, a cytosolic DNA sensor), CD25 and granzyme-B in the HIV-positive compared to HIV-negative, p<0.05(Figure 1B). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/221325v1_fig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1a4757forg.highwire.dtl.DTLVardef@1e2236org.highwire.dtl.DTLVardef@582f4borg.highwire.dtl.DTLVardef@188f376_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Characterization of coronary plaques. Representative coronary plaques from three HIV-positive and three HIV-negative individuals were stained with H&E and Movat stain (A). Plaque area (m2) and % plaque stenosis were measured and calculated in 6 individuals per group (B). Statistical analysis, Mann-Whitney; ns not significant C_FIG ConclusionsIncreased inflammation within the coronary plaques of PLWH is characterized by more innate and adaptive immune cells. Higher STING expression in PLWH suggests that immune response to viral antigens within the plaque might be a driver above other stimulants. STING inhibitors are available and could be investigated as a future therapeutic target in PWH if these results are replicated with a larger number of plaques. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/221325v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@27fa00org.highwire.dtl.DTLVardef@8e4a65org.highwire.dtl.DTLVardef@1b65320org.highwire.dtl.DTLVardef@10b7c9a_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIImmunohistochemical and fluorescent stains combined with GeoMx(R) digital spatial profiling allowed for deep characterization of immune cells within intact coronary plaques and perivascular adipose tissue C_LIO_LICoronary plaques from HIV-positive persons had higher proportion of CD163+ immune cells compared to HIV-negative persons C_LIO_LIDifferential protein expression of immune-rich regions of interest within intact 5m sections of coronary plaques revealed higher levels of stimulator of interferon gamma (STING) in HIV-positive persons C_LI

immunology↗