Biology subjects

Sheikh, A. A.

Publications and source records attributed to Sheikh, A. A..

3 recordsLinked to original sources

bioRxiv2024

Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity

Adaptive immune responses protect against multiple classes of pathogens, including viral, bacterial, fungal, and helminth infections. In all these settings, CD4+ T follicular helper (Tfh) cells tailor high-affinity class-switched B cells responses. How Tfh lineage sovereignty is established while allowing for this context-specific functional heterogeneity is unclear. Here, we identify Tfh transcriptional networks in response to diverse infections. While Bcl-6 is the transcriptional linchpin of the core Tfh signature, this is overlayed with pathogen-specific transcriptional modules that shape Tfh function. Cytokine-transcriptional Tfh programing in mouse and human lymphoid tissue demonstrated that type I interferon and TGF{beta} signaling direct individual Tfh subpopulations to instruct B cell output. Here, we provide a transcriptional map and cell surface resource to interrogate Tfh diversity in humans and mice. This resource can be leveraged to further understand the origins of immune flexibility, perform immune monitoring in infection and antibody-mediated diseases and to develop context-specific vaccines. ONE-SENTENCE SUMMARYDalit, Tan and colleagues provide a resource that functionally and transcriptionally profiles T follicular helper cells (Tfh) during diverse pathogen responses to reveal a blueprint for transcriptional flexibility and new tools to interrogate Tfh heterogeneity in mice and humans.

immunology↗

bioRxiv2022

Improved sensitivity and resolution of ATAC-seq differential DNA accessibility analysis

Eukaryotic genomes are packaged into chromatin, and the extent of its compaction must be modulated to allow several biological processes such as gene transcription. The regulatory elements of expressed genes are typically in relatively accessible chromatin, and several studies have revealed a reliable correlation between the abundance of mRNA transcripts and the degree of DNA accessibility at the regulatory elements of their coding genes. In consequence, the genome-wide profiling of DNA accessibility by methods such as ATAC-seq can help in the study of gene regulatory networks by serving as a proxy for gene expression and by helping identify important gene cis-regulatory elements and the trans-acting factors that bind them. The predominant approach used to identify differentially accessible genomic loci from ATAC-seq data obtained in two conditions of interest is comparable to that employed in RNA-seq gene expression profiling studies: accessible regions are identified through peak calling and treated like "genes", then sequenced DNA fragments (originating from two neighboring transposase insertion events) that overlap them are counted and subjected to abundance modeling, which then allows to identify those that have a significant difference between the two conditions. We reasoned that this approach could be improved in terms of sensitivity and resolution by introducing two changes: bypassing peak calling, using instead a genome-wide sliding window quantification approach, and counting transposase insertion sites, instead of fragments originating from two neighboring insertion sites. We present the development of this approach, which we term "widaR", for Window- and Insertion-based Differential Accessibility in R, using a murine skeletal myoblast differentiation dataset. Reproducible R code is provided.

genomics↗

bioRxiv2021

Heterogeneous Tfh cell populations that develop during enteric helminth infection predict the quality of type 2 protective response

T follicular helper (Tfh) cells are an important component of the germinal centre (GC)-mediated humoral immunity. Yet, how regulation of Tfh- GC responses impacts on effective responses to helminth infection are poorly understood. Here we show that chronic helminth Trichuris muris infection fails to induce Tfh-GC B cell responses, with Tfh cells expressing T-bet and IFN-{gamma}. In contrast, Tfh cells that express GATA-3 and IL-4 dominate responses to an acute, resolving infection. Accordingly, heightened expression and increased chromatin accessibility of Th1- and Th2 cell-associated genes is observed in chronic and acute induced Tfh cells, respectively. However, both acute and chronic Tfh cell populations retained the capacity to produce IL-21 in spite of the Th-biased response. Blockade of Tfh-GC interactions impaired type 2 immunity, highlighting the protective role of GC-dependent Th2-like Tfh cell responses against helminths. Collectively, these results provide new insights into the protective roles of Tfh-GC responses and identify distinct transcriptional and epigenetic features of Tfh cells that emerge during resolving or chronic helminth infections. Author summaryAbout a quarter of the world population is afflicted with parasitic worm infection. Although deworming drugs can reduce the levels of the infection, they fail to prevent reinfections. Therefore, the most sustainable goal is to develop vaccines against human helminth parasites, which has been extremely challenging due to the lack of understanding of host-parasite interactions. While the protective roles of T helper 2 (Th2) cells are well established, the regulation of T follicular helper (Tfh) cells and their roles during helminth infection remain poorly defined. In this study, we describe the differential regulation of Tfh cell responses during chronic non-protective vs acute protective responses during helminth infection. We show that Tfh cells during chronic infection are rare and have strikingly different characteristics to acute-induced Tfh cells, which appear to be more like Th2 cells. Specifically, we show that blockade of Th2-like Tfh cell response during acute infection results in the host failing to expel the worms. Our study identifies that Tfh cell populations that emerge during chronic and acute infection are strikingly heterogeneous and critically important in mediating protective immune responses against helminths.

immunology↗