Biology subjects

Bejjani, A. T.

Publications and source records attributed to Bejjani, A. T..

4 recordsLinked to original sources

bioRxiv2025

Gene regulatory network determinants of rapid recall in human memory CD4+ T cells

Rapid recall is the hallmark of memory T cells. While naive cells require days to mount effector responses to new threats, antigen-experienced memory cells produce cytokines within hours of repeat encounter. Memory establishment and the control of rapid recall across lifespan is poorly understood. Epigenetic poising is a likely mechanism. Compared to naive, memory cells exhibit enhanced chromatin accessibility proximal to rapid recall genes, but the transcription factors (TFs) that establish, maintain and utilize these putative regulatory elements are unknown. We leverage single-nuclei (sn)multiome-seq (snRNA-seq and snATAC-seq) to characterize the dynamic activation responses of CD4+ T cell subsets and (2) reconstruct the underlying gene regulatory networks. Memory-associated TFs (MAF, PRDM1, RUNX2, SMAD3, KLF6) were predicted to orchestrate rapid recall. KLF6 binding to its predicted target genes was confirmed by ChIP-seq, while the memory-associated activities of all five factors replicated in independent scRNA-seq studies. Integrating GWAS data, we nominate CD4+ T cell populations and gene regulatory mechanisms that might underly genetic risk to immune-mediated diseases.

systems biology↗

bioRxiv2024

Accessible chromatin maps of inflammatory bowel disease intestine nominate cell-type mediators of genetic disease risk

Inflammatory Bowel Disease (IBD) is a chronic autoinflammatory disorder with rising incidence in pediatrics. TNFa inhibition (TNFi) is the first-line biologic therapy in children, but many do not achieve mucosal healing. Identifying which patients will benefit from TNFi and the underlying nonresponse mechanisms is critical. We built a novel resource: whole genome sequencing linked to multiome-seq (single-nuclei transcriptome and chromatin accessibility) of intestinal biopsies from a cohort of children with IBD, whose TNFi response was defined by mucosal healing. Our study uncovers links between IBD genetic risk and TNFi response. First, classifiers integrating genetic data with clinical variables identified the IBD polygenic risk score as a top predictor of TNFi response. Second, multiome-seq analysis implicated IBD risk variants in persistent cytokine signaling in monocytes, macrophage and fibroblasts of nonresponders. These data reveal genetic mechanisms of treatment response in pediatric IBD and suggest alternative therapeutic approaches for TNFi nonresponders.

genomics↗

bioRxiv2023

Elevated CD153 Expression on Aged T Follicular Helper Cell is Vital for B cell Responses

Our recent data showed that an aberrant IL-10-producing T follicular helper population (Tfh10) accumulates dramatically with age and is associated with age-related declines in vaccine responsiveness. Through single cell gene expression and chromatin accessibility analysis of IL-10+ and IL-10- memory CD4+ T cells from young and aged mice, we identified increased expression of CD153 on aged Tfh and Tfh10 cells. Mechanistically, we linked inflammaging (increased IL-6 levels) to elevated CD153 expression of Tfh cells through c-Maf. Surprisingly, blockade of CD153 in aged mice significantly reduced their vaccine-driven antibody response, which was associated with decreased expression of ICOS on antigen-specific Tfh cells. Combined, these data show that an IL-6/c-Maf/CD153 circuit is critical for maintaining ICOS expression. Thus, although overall Tfh-mediated B cell responses are reduced in the context of vaccines and aging, our data suggest that elevated expression of CD153 on Tfh cells potentiates the remaining Tfh function in aged mice.

immunology↗

bioRxiv2023

An atlas of gene regulatory networks for T memory cells in youth and old age

Aging profoundly affects immune-system function, promoting susceptibility to pathogens, cancers and chronic inflammation. We previously identified a population of IL-10-producing, T follicular helper-like cells ("Tfh10"), linked to suppressed vaccine responses in aged mice. Here, we integrate single-cell (sc)RNA-seq, scATAC-seq and genome-scale modeling to characterize Tfh10 - and the full CD4+ memory T cell (CD4+TM) compartment - in young and old mice. We identified 13 CD4+TM populations, which we validated through cross-comparison to prior scRNA-seq studies. We built gene regulatory networks (GRNs) that predict transcription-factor control of gene expression in each T-cell population and how these circuits change with age. Through integration with pan-cell aging atlases, we identified intercellular-signaling networks driving age-dependent changes in CD4+TM. Our atlas of finely resolved CD4+TM subsets, GRNs and cell-cell communication networks is a comprehensive resource of predicted regulatory mechanisms operative in memory T cells, presenting new opportunities to improve immune responses in the elderly.

immunology↗