Biology subjects

Hailes, L.

Publications and source records attributed to Hailes, L..

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↗

bioRxiv2023

Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity

ObjectivesB cells drive the production of autoreactive antibody-secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjogrens syndrome, causing long-term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibody. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-1 could deplete ASCs in autoimmune conditions in vivo and in vitro. MethodsUse of a BMI-1 inhibitor in both mouse and human autoimmune settings was investigated. Lyn-/- mice, a model of SLE, were treated with the BMI-1 small molecule inhibitor PTC-028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-028 on ASCs derived from Sjogrens syndrome patients evaluated. ResultsBMI-1 inhibition significantly decreased splenic and bone marrow ASCs in Lyn-/-mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti-DNA IgG. PTC-028 was also efficacious in reducing ex vivo plasma cell survival from both Sjogrens syndrome patients and age-matched healthy donors. ConclusionThese data provide evidence that inhibiting BMI-1 can deplete ASC in a variety of contexts and thus BMI-1 is a viable therapeutic target for antibody-mediated autoimmune diseases.

immunology↗

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↗