Biology subjects

Yap, G. S.

Publications and source records attributed to Yap, G. S..

3 recordsLinked to original sources

bioRxiv2025

Senescent CD8+ T Effector Memory Cells are Functionally Impaired, Enriched in Aging and Disease, and a Barrier to Immunotherapy

Senescent cells play important roles in various biological processes that promote fitness and health, however, their timely elimination by immune cells is critical to maintain tissue homeostasis and prevent disease. Despite this, senescent cells progressively accumulate systemically with age, suggesting that certain immune cells also become senescent and dysfunctional during aging. Supporting this, we previously demonstrated that CD8 T cells, immune cells capable of targeting senescent cells, increasingly develop characteristics of senescence with advancing age in humans. Here, we further characterized the senescence state of human SA-{beta}Gal-expressing CD8 T effector cells, their functional capabilities, and their involvement in aging and disease. Single-cell RNA sequencing revealed that SA-{beta}Gal-expressing CD8 T cells with unique transcriptional signatures develop in all stages of T cell differentiation, including in effector memory (EM) T cells. SA-{beta}Gal-expressing CD8 TEM cells expressed various classical markers of senescence and were significantly impaired in their ability to proliferate, produce cytokines, and eliminate senescent human stromal cells, compared to CD8 TEM cells with low SA-{beta}Gal activity. Gene signatures of senescent SA-{beta}Gal-expressing CD8 TEM cells were enriched in CD8 T cells from older human donors, patients with age-related disorders, cancer, and smokers. Furthermore, our results demonstrate that T cell senescence is distinct from and dominant over T cell exhaustion, limiting the response of CD8 TEM cells to immunotherapy. Collectively, our study demonstrates that the senescence state impairs the functions of CD8 TEM cells and reveals the involvement of senescent and dysfunctional CD8 TEM cells in aging, disease, exposure to toxins, and responses to immunotherapy.

cell biology↗

bioRxiv2024

Cohesin-mediated chromatin remodeling controls the differentiation and function of conventional dendritic cells

The cohesin protein complex extrudes chromatin loops, stopping at CTCF-bound sites, to organize chromosomes into topologically associated domains, yet the biological implications of this process are poorly understood. We show that cohesin is required for the post-mitotic differentiation and function of antigen-presenting dendritic cells (DCs), particularly for antigen cross-presentation and IL-12 secretion by type 1 conventional DCs (cDC1s) in vivo. The chromatin organization of DCs was shaped by cohesin and the DC-specifying transcription factor IRF8, which controlled chromatin looping and chromosome compartmentalization, respectively. Notably, optimal expression of IRF8 itself required CTCF/cohesin-binding sites demarcating the Irf8 gene. During DC activation, cohesin was required for the induction of a subset of genes with distal enhancers. Accordingly, the deletion of CTCF sites flanking the Il12b gene reduced IL-12 production by cDC1s. Our data reveal an essential role of cohesin-mediated chromatin regulation in cell differentiation and function in vivo, and its bi-directional crosstalk with lineage-specifying transcription factors.

immunology↗

bioRxiv2024

The GPI sidechain of Toxoplasma gondii prevents parasite pathogenesis

Glycosylphosphatidylinositols (GPIs) are highly conserved anchors for eukaryotic cell surface proteins. The apicomplexan parasite, Toxoplasma gondii, is a widespread intracellular parasite of warm-blooded animals whose plasma membrane is covered with GPI-anchored proteins, and free GPIs called GIPLs. While the glycan portion is conserved, species differ in sidechains added to the triple mannose core. The functional significance of the Glc1,4GalNAc{beta}1-sidechain reported in Toxoplasma gondii has remained largely unknown without an understanding of its biosynthesis. Here we identify and disrupt two glycosyltransferase genes and confirm their respective roles by serology and mass spectrometry. Parasites lacking the sidechain on account of deletion of the first glycosyltransferase, PIGJ, exhibit increased virulence during primary and secondary infections, suggesting it is an important pathogenesis factor. Cytokine responses, antibody recognition of GPI-anchored SAGs, and complement binding to PIGJ mutants are intact. In contrast, the scavenger receptor CD36 shows enhanced binding to PIGJ mutants, potentially explaining a subtle tropism for macrophages detected early in infection. Galectin-3, which bind GIPLs, exhibits a slight enhancement of binding to PIGJ mutants, and the protection of galectin-3 knockout mice from lethality suggests that{Delta} pigj parasite virulence in this context is sidechain dependent. Parasite numbers are not affected by{Delta} pigj early in the infection in wildtype mice, suggesting a breakdown of tolerance. However, increased tissue cysts in the brains of mice infected with{Delta} pigj parasites indicate an advantage over wildtype strains. Thus, the GPI sidechain of T. gondii plays a crucial and diverse role in regulating disease outcome in the infected host. SummaryThe functional significance of sidechain modifications to the GPI anchor is yet to be determined because the glycosyltransferases responsible for these modifications have not been identified. Here we present identification and characterization of both T. gondii GPI sidechain-modifying glycosyltransferases. Removal of the glycosyltransferase that adds the first GalNAc to the sidechain results in parasites without a sidechain on the GPI, and increased parasite virulence. Loss of the second glycosyltransferase results in a sidechain with GalNAc alone, and no glucose added, and has negligible effect on parasite virulence. This indicates GPI sidechains as fundamental to host-parasite interactions.

microbiology↗