Biology subjects

Ceglia, S.

Publications and source records attributed to Ceglia, S..

4 recordsLinked to original sources

bioRxiv2024

Distinct components of nucleoside-modified messenger RNA vaccines cooperate to instruct efficient germinal center responses

Nucleoside-modified mRNA vaccines elicit protective antibodies through their ability to promote T follicular helper (Tfh) cells. The lipid nanoparticle (LNP) component of mRNA vaccines possesses inherent adjuvant activity. However, to what extent the nucleoside-modified mRNA can be sensed and contribute to Tfh cell responses remains largely undefined. Herein, we deconvoluted the signals induced by LNP and mRNA that instruct dendritic cells (DCs) to promote Tfh cell differentiation. We demonstrated that the nucleoside-modified mRNA drives the production of type I interferons that act on DCs to induce their maturation and the induction of Th1-biased Tfh responses. Conversely, LNP favors the acquisition of a Tfh cell-inducing program in DCs, a stronger Th2 polarization in Tfh cells, and allows for rapid mRNA translation by DCs within the draining lymph node. Our work unravels distinct adjuvant features of mRNA and LNP necessary for the induction of Tfh cells, with implications for vaccine design.

immunology↗

bioRxiv2024

Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during Clostridioides difficile infection in the large intestine

Metabolic byproducts of the intestinal microbiota are crucial in maintaining host immune tone and shaping inter-species ecological dynamics. Among these metabolites, succinate is a driver of tuft cell (TC) differentiation and consequent type 2 immunity-dependent protection against invading parasites in the small intestine. Succinate is also a growth enhancer of the nosocomial pathogen Clostridioides difficile in the large intestine. To date, no research has shown the role of succinate in modulating TC dynamics in the large intestine, or the relevance of this immune pathway to C. difficile pathophysiology. Here we reveal the existence of a three-way circuit between commensal microbes, C. difficile and host epithelial cells which centers around succinate. Through selective microbiota depletion experiments we demonstrate higher levels of type 2 cytokines leading to expansion of TCs in the colon. We then demonstrate the causal role of the microbiome in modulating colonic TC abundance and subsequent type 2 cytokine induction using rational supplementation experiments with fecal transplants and microbial consortia of succinate-producing bacteria. We show that administration of a succinate-deficient Bacteroides thetaiotaomicron knockout ({Delta}frd) significantly reduces the enhanced type 2 immunity in mono-colonized mice. Finally, we demonstrate that mice prophylactically administered with the consortium of succinate-producing bacteria show reduced C. difficile-induced morbidity and mortality compared to mice administered with heat-killed bacteria or the vehicle. This effect is reduced in a partial tuft cell knockout mouse, Pou2f3+/-, and nullified in the tuft cell knockout mouse, Pou2f3-/-, confirming that the observed protection occurs via the TC pathway. Succinate is an intermediary metabolite of the production of short-chain fatty acids, and its concentration often increases during dysbiosis. The first barrier to enteric pathogens alike is the intestinal epithelial barrier, and host maintenance and strengthening of barrier integrity is vital to homeostasis. Considering our data, we propose that activation of TC by the microbiota-produced succinate in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by intestinal pathogens.

immunology↗

bioRxiv2023

Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to control local Peyer's patch development

Lymphoid tissue inducer (LTi) cells develop during intrauterine life and rely on developmental programs to initiate the organogenesis of secondary lymphoid organs (SLOs). This evolutionary conserved process endows the fetus with the ability to orchestrate the immune response after birth and to react to the triggers present in the environment. While it is established that LTi function can be shaped by maternal-derived cues and is critical to prepare the neonate with a functional scaffold to mount immune response, the cellular mechanisms that control anatomically distinct SLO organogenesis remain unclear. We discovered that LTi cells forming Peyers patches, gut-specific SLOs, require the coordinated action of two migratory G protein coupled receptors (GPCR) GPR183 and CCR6. These two GPCRs are uniformly expressed on LTi cells across SLOs, but their deficiency specifically impacts Peyers patch formation, even when restricted to fetal window. The unique CCR6 ligand is CCL20, while the ligand for GPR183 is the cholesterol metabolite 7,25-Dihydroxycholesterol (7,25-HC), whose production is controlled by the enzyme cholesterol 25-hydroxylase (CH25H). We identified a fetal stromal cell subset that expresses CH25H and attracts LTi cells in the nascent Peyers patch anlagen. GPR183 ligand concentration can be modulated by the cholesterol content in the maternal diet and impacts LTi cell maturation in vitro and in vivo, highlighting a link between maternal nutrients and intestinal SLO organogenesis. Our findings revealed that in the fetal intestine, cholesterol metabolite sensing by GPR183 in LTi cells for Peyers patch formation is dominant in the duodenum, the site of cholesterol absorption in the adult. This anatomic requirement suggests that embryonic, long-lived non-hematopoietic cells might exploit adult metabolic functions to ensure highly specialized SLO development in utero.

immunology↗

bioRxiv2020

Intracellular sterol sensing controls intestinal B cell differentiation

Intestinal B cell responses are critical for the maintenance of gut homeostasis, yet environmental signals that control B cell metabolism and effector function remain poorly characterized. Here, we show that Peyers patches germinal center (GC) B cells are sensitive to 25-hydroxycholesterol (25-HC), an oxidized metabolite of cholesterol produced by the enzyme cholesterol 25-hydroxylase (CH25H). In mice lacking CH25H, antigen-specific GC B cells show an increased cholesterol metabolic signature and preferentially differentiate in plasma cells (PCs), thereby inducing a stronger intestinal IgA response upon immunization or infection. GC B cells express the sterol sensor SREBP2 and use it to sense 25-HC. Deletion of SREBP2 from GC B cells prevents PC differentiation and forces the maintenance of GC identity. GC localized oxysterol production by follicular dendritic cells is central in dictating GC metabolism and imposing B cell fate. Our findings show that the 25-HC-SREBP2 axis shapes B cell effector function in intestinal lymphoid organs and indicate that dietary cholesterol can instruct local B cell response.

immunology↗