Biology subjects

Sanjabi, S.

Publications and source records attributed to Sanjabi, S..

3 recordsLinked to original sources

bioRxiv2025

Intratumoral cDC1-T Cell Clusters Serve as Sites of Local Costimulation to Enhance CTL-Mediated Tumor Rejection

T cells are essential for anti-tumor immunity, but their ability to eliminate tumors depends on coordinated interactions with type 1 conventional dendritic cells (cDC1s). While cDC1s are known for cross-presenting tumor-derived antigens in lymph nodes to prime CD8+ T cells, their role within the tumor itself remains less well understood. Here, we use the Skin Tumor Array by Micro-Poration (STAMP) model to investigate how cDC1-T cell interactions shape immune responses and influence tumor fate. Our data reveal that it is the spatial distribution of both cDC1s and T cells that determines whether a tumor can be rejected. We defined three primary immunotypes based on the spatial distribution of T cells and cDC1s: T cell-inflamed/dendritic cell-inflamed (TC-In/DC-In) tumors, where T cells and cDC1s co-infiltrate the tumor; T cell-inflamed/dendritic cell-excluded (TC-In/DC-Ex) tumors, where T cells infiltrate but cDC1s remain at the periphery; and T cell-excluded/dendritic cell-excluded (TC-Ex/DC-Ex) tumors, which lack both cDC1 and T cell infiltration. Notably, TC-In/DC-In tumors are more likely to undergo rejection, whereas TC-In/DC-Ex tumors persist despite T cell infiltration. Within TC-In/DC-In tumors, cDC1s engage in direct interactions with T cells, upregulate co-stimulatory molecules, and sustain effector T cell responses, while cDC1s in TC-In/DC-Ex tumors express higher migration-associated genes, suggesting a propensity to exit the tumor. We further show that chemokine modulation, particularly through CXCL9, CCL5, and XCL1, can reshape immune infiltration patterns to promote intra-tumoral cDC1-T cell clustering and improve tumor rejection. These findings underscore the unexpectedly important role of cDC1 positioning and function in sustaining effective anti-tumor immunity and highlight spatially organized cDC1-T cell clusters as critical hubs for local T cell activation.

immunology↗

bioRxiv2021

Single cell genome sequencing of laboratory mouse microbiota improves taxonomic and functional resolution of this model microbial community

Laboratory mice are widely studied as models of mammalian biology, including the microbiota. However, much of the taxonomic and functional diversity of the mouse gut microbiome is missed in current metagenomic studies, because genome databases have not achieved a balanced representation of the diverse members of this ecosystem. Towards solving this problem, we used flow cytometry and low-coverage sequencing to capture the genomes of 764 single cells from the stool of three laboratory mice. From these, we generated 298 high-coverage microbial genome assemblies, which we annotated for open reading frames and phylogenetic placement. These genomes increase the gene catalog and phylogenetic breadth of the mouse microbiota, adding 135 novel species with the greatest increase in diversity to the Muribaculaceae and Bacteroidaceae families. This new diversity also improves the read mapping rate, taxonomic classifier performance, and gene detection rate of mouse stool metagenomes. The novel microbial functions revealed through our single-cell genomes highlight previously invisible pathways that may be important for life in the murine gastrointestinal tract.

microbiology↗

bioRxiv2017

Development of Inflammatory Bowel Disease is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice

The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regards to function. To investigate microbiome mediated disease mechanisms and discover early biomarkers of IBD, we conducted a longitudinal metagenomic investigation in an established mouse model of IBD, where dampened TGF-{beta} signaling in T cells leads to peripheral immune activation, weight loss, and severe colitis. IBD development is associated with abnormal gut microbiome temporal dynamics, including dampened acquisition of functional diversity and significant differences in abundance trajectories for KEGG modules such as glycosaminoglycan degradation, cellular chemotaxis, and type III and IV secretion systems. Most differences between sick and control mice emerge when mice begin to lose weight and heightened T cell activation is detected in peripheral blood. However, lipooligosaccharide transporter abundance diverges prior to immune activation, indicating that it could be a pre-disease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundance of particular taxa, including several species of Bacteroides, correlate with immune activation. These discoveries were enabled by our use of generalized linear mixed effects models to test for differences in longitudinal profiles between healthy and diseased mice while accounting for the distributions of taxon and gene counts in metagenomic data. These findings demonstrate that longitudinal metagenomics is useful for discovering potential mechanisms through which the gut microbiome becomes altered in IBD.\n\nImportanceIBD patients harbor distinct microbial communities with different functional capabilities compared to healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading up to disease onset. By performing weekly metagenomic sequencing and mixed effects modeling on an established mouse model of IBD, we identified several functional pathways encoded by the gut microbiome that covary with host immune status. These pathways are novel early biomarkers that may either enable microbes to live inside an inflamed gut or contribute to immune activation in IBD mice. Future work will validate the potential roles of these microbial pathways in host-microbe interactions and human disease. This study is novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development.

microbiology↗