Biology subjects

Zaini, A.

Publications and source records attributed to Zaini, A..

6 recordsLinked to original sources

bioRxiv2024

MLL1 directs gut-associated antibody responses to helminth and bacterial infections

Soil-transmitted helminths are one of the most common infections globally, yet how to promote effective gut-associated humoral responses is not well understood. We identify the histone methyltransferase MLL1 as a key target to promote IgA-driven responses. Mll1 was increased in germinal center B cells in gut-associated lymphoid tissues, and Mll1-deficiency led to changes in the histone modification H3K4me3 on key B cell and immune-regulatory genes. Correspondingly, MLL1-deficient B cells had defective germinal centers and IgG1 in response to the helminth Trichuris muris. Yet, Mll1f/fCd23cre/+ mice expelled worms more rapidly compared to control mice. Accelerated worm clearance correlated with elevated IgA+ plasma cells, as well as both serum and fecal IgA. RNA-sequencing identified CCR9 as a key MLL1-regulated molecule. As such, Mll1f/fCd23cre/+ mice infected with T. muris had increased IgA+CCR9+ PC localized in the large intestine. Regulation of IgA by MLL1 was confirmed beyond T. muris infection. In vitro cultures confirmed Mll1-deficiency increased IgA+ plasma cells in a B cell-intrinsic manner, and IgA production was also increased in Mll1f/fCd23cre/+ mice infected with the bacterium C. rodentium. This study reveals MLL1 as a key target to promote IgA responses to gut-associated infections.

immunology↗

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

Helminth infection driven gastrointestinal hypermotility is independent of eosinophils and mediated by alterations in smooth muscle instead of enteric neurons

Intestinal helminth infection triggers a type 2 immune response that promotes a weep-and sweep response characterised by increased mucus secretion and intestinal hypermotility, which function to dislodge the worm from its intestinal habitat. Recent studies have discovered that several other pathogens cause intestinal dysmotility through major alterations to the immune and enteric nervous systems (ENS), and their interactions, within the gastrointestinal tract. However, the involvement of these systems has not been investigated for helminth infections. Eosinophils represent a key cell type recruited by the type 2 immune response and alter intestinal motility under steady-state conditions. Our study aimed to investigate whether intestinal dysmotility driven by murine hookworm, Nippostrongylus brasiliensis, infection involves eosinophils and how the ENS and smooth muscles of the gut are impacted. Eosinophil deficiency did not influence helminth-induced intestinal hypermotility and hypermotility did not involve gross structural or functional changes to the ENS. Hypermotility was instead associated with a dramatic increase in smooth muscle thickness and contractility. In summary our data indicate that, in contrast to other pathogens, helminth-induced intestinal hypermotility is driven by largely by myogenic, rather than neurogenic, alterations with such changes occurring independently of eosinophils. (<300 words) Author SummaryIntestinal helminth infection is a global threat to those living in poverty without adequate sanitation. Expulsion of intestinal worms is driven by a host type 2 immune response, characterised by increased eosinophils, that results in the intestinal hypermotility and mucus secretion that dislodge the worm from its luminal habitat. Intestinal motility is largely controlled by the local enteric nervous system (ENS) and can be regulated by close interactions between neurons and intestinal immune cells. Utilising Nippostrongylus brasiliensis as a model of murine hookworm infection, we investigated the contribution of the ENS and eosinophils to intestinal hypermotility and worm expulsion. Despite the critical role of the ENS in regulating typical intestinal function, very little alteration to ENS structure or function was observed following N. brasiliensis infection. Instead, infected animals displayed dramatically increased smooth muscle thickness and contractile strength. Neither helminth-induced intestinal hypermotility nor altered smooth muscle morphology required eosinophils. Our findings reveal that, in contrast to other intestinal pathogens, myogenic rather than neurogenic alterations drive small intestinal hypermotility and pathogen expulsion following hookworm infection. (<200 words)

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↗

bioRxiv2021

c-Rel is required for IL-33-dependent activation of ILC2s

Group 2 innate lymphoid cells (ILC2s) are emerging as important cellular regulators of homeostatic and disease-associated immune processes. The cytokine interleukin-33 (IL-33) promotes ILC2-dependent inflammation and immunity, with IL-33 having been shown to activate NF-{kappa}B in a wide variety of cell types. However, it is currently unclear which NF-{kappa}B members play an important role in IL-33-dependent ILC2 biology. Here, we identify the NF-{kappa}B family member c-Rel as a critical component of the IL-33-dependent activation of ILC2s. Although c-Rel is dispensable for ILC2 development, it is critical for ILC2 function in the lung, with c-Rel-deficient (c-Rel-/-) mice resistant to papain- and IL-33-induced lung inflammation. We also show that the absence of c-Rel reduces the IL-33-dependent expansion of ILC2 precursors and lower levels of IL-5 and IL-13 cytokine production by mature ILC2s in the lung. Together, these results identify the IL-33-c-Rel axis as a central control point of ILC2 activation and function.

immunology↗

bioRxiv2019

The lysine methyltransferase DOT1L controls CD4+ T cell differentiation and plasticity

CD4+ T helper (Th) cell differentiation is controlled by lineage-specific expression of transcription factors and effector proteins, as well as silencing of lineage-promiscuous genes. Lysine methyltransferases (KMTs) comprise a major class of epigenetic enzymes that are emerging as important regulators of Th cell biology. Here, we show that the KMT DOT1L regulates Th cell function and lineage integrity. DOT1L-dependent dimethylation of lysine 79 of histone H3 (H3K79me2) is associated with lineage-specific gene expression. However, DOT1L-deficient Th cells overproduce IFN-{gamma} under lineage-specific and lineage-promiscuous conditions. Consistent with the increased IFN-{gamma} response, mice with a T cell-specific deletion of DOT1L are susceptible to infection with the helminth parasite Trichuris muris and resistant to the development of allergic lung inflammation. These results identify a central role for DOT1L in Th cell lineage commitment and stability, and suggest that inhibition of DOT1L may provide a novel therapeutic strategy to limit type 2 immune responses.

immunology↗