Webinars Oncoimmuno FRJP

Bcells/antibodies
23rd april

Functions of two humoral memory populations and their generation mechanisms
→ Read the abstract

The successful establishment of humoral memory response depends on at least two layers of defense. Pre-existing protective antibodies secreted by long-lived plasma cells (LLPCs) act as a first line of defense against reinfection (“constitutive humoral memory”). Previously, a second line of defense in which pathogen-experienced memory B cells are rapidly reactivated to produce antibodies (“reactive humoral memory”), was considered as simply a back-up system for the first line (particularly for re-infection with homologous viruses). By using influenza model system, we found that, in the case of re-infection with similar but different strains of viruses, the constitutive humoral memory (LLPCs) is no more protective, while reactive humoral memory (memory B cells) plays a crucial role. These somewhat differential roles of LLPCs and memory B cells promoted us to look for the generation mechanisms of the two compartments in germinal centers (GCs). We proposed the affinity instruction model, whereby a high-affinity or low-affinity BCR is the primary determinant for LLPC or memory B cell generation, respectively. I will present the experimental data to support this model.    

Tomohiro Kurosaki, MD, PhD
RIKEN Center for Integrative Medical Sciences, Osaka University, Japan

Unveiling the molecular basis of T cell malfunctions and disorders using multi-omics approaches
→ Read the abstract

T cells play a central role in adaptive immunity. Although the T cell antigen receptor (TCR) primarily controls T cell physiology, it does not work in isolation and the signals it triggers are tuned by a multitude of other surface receptors that deliver positive (costimulators) and negative (coinhibitors) informations about the state of activation of antigen-presenting cells (primarily dendritic cells). Therapeutic antibodies (immune-checkpoint inhibitors) blocking coinhibitors have become standard treatment for several malignant conditions, leading to a revival in the study of T cell coinhibition and costimulation. However, we lack a satisfying comprehension of the way T cells integrate inputs from multiple signalling pathways and use inter-pathway crosstalk to make informed decisions. To make sense of the formidable complexity of the signal transduction networks involved in T cell activation and the role played by the different types of dendritic cells in T cell activation, we combined “omic” and mouse genetics. It allowed us to decipher in a time-resolved and quantitative manner the dynamics of the protein signaling complexes (signalosomes) that assemble in primary T cells following physiologic TCR engagement. To further illustrate the interest of multi-omics approaches, I will present recent data generated with several Japanese collaborators and demonstrating how corrupted LAT signalosomes lead to an inflammatory and autoimmune disease recapitulating human IgG4-related disease.

Bernard Malissen, PhD
Marseille-Luminy Immunology center (CIML), France

ILC
14th may

Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis
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Pulmonary fibrosis (PF) is characterized by inflammation and collagen deposition in the alveolar interstitium, resulting in dyspnea and death. Patients with PF often exhibit decreased levels of IFNγ, leading to fibroblast proliferation and collagen synthesis. Our study using Ifngr1-/-Rag2-/- mice, which lack mechanisms to suppress ILC2s and ILC3s, revealed spontaneous and severe PF development. Levels of surfactant protein D (SP-D), a common clinical biomarker reflecting disease activity, increased and the saturation of percutaneous oxygen (SpO2) levels significantly decreased in aged mice. In these mice, the IL-33hiIL-13hi ILC2 subpopulation increased during the disease-onset phase before collagen production commenced. Because fibrosis disappears in ILC-deficient or IL-33-deficient mice, IL-33-mediated activation of ILC2s seems to be critical for fibrosis. ILC2s were found to directly induce collagen production by fibroblasts in vitro, and pathogenic fibroblasts began producing IL-33 in the chronic phase, presumably establishing a positive feedback loop between fibroblasts and ILC2s leading to irreversible fibrosis. Finally, the increased expression of IL1RL1 (IL-33R) and IL13, along with decreased expression of IFNGR1 were confirmed in ILC2s from idiopathic pulmonary fibrosis patients, suggesting that dysregulation of ILC2s may also cause endogenous fibrosis in humans.

In this seminar, I'll discuss current research that focuses on how ILC3 and neutrophils contribute to the sustained activation of ILC2 through IL-33 in the context of PF.

Kazuyo Moro, PhD
RIKEN Center for Integrative Medical Sciences, Japan
Osaka University, Japan

Enhanced NK cell-poiesis in metabolic-dysfunction-associated steatohepatitis
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Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by lipid accumulation and insulin resistance, explained by the "multiple hit" hypothesis. Factors such as lifestyle, the gut microbiome, dietary habits, and obesity play significant roles. These conditions lead to changes in the gut microbiota, which increase hepatic lipogenesis and decrease the inhibition of lipolysis in adipose tissue. This results in an excess of free fatty acids in the liver and subsequent fat accumulation. The accumulated fat causes lipotoxicity, impairing mitochondrial function and leading to the production of reactive oxygen species and stress on the endoplasmic reticulum. Coupled with insulin resistance, this condition also increases the absorption of lipopolysaccharides (LPS) from the gut due to enhanced intestinal permeability associated with an altered gut microbiome. The resulting cellular damage triggers immune cell infiltration, inflammation, and fibrogenesis. MASH is increasingly becoming a primary cause of hepatocellular carcinoma (HCC) development. The role of NK cells in MASH remains a topic of debate, as their impact on disease progression may be both protective and harmful. NK cells develop in the bone marrow (BM), where they mature and acquire functional capabilities before dispersing to various tissues, including the liver, where they are the predominant population of lymphocytes. Using induced MASH models through two different diets, we observed an increase in the frequency and numbers of specific hepatic NK subsets, characterized by "immature" and activated markers, along with a significant increase in IFNγ secretion. We have identified the molecular mechanisms behind liver NK cell recruitment and accumulation in MASH. We propose a cellular dialogue between BM monocytes and NK precursors involving the IL-15 and osteopontin pathways, partially driven by endotoxemia. This tripartite gut-liver-BM axis regulates the influx of innate immune populations recruited to the liver, impacting disease progression.

Rachel Golub, PhD
Pasteur Institute, France

Mucosal Immunology
18th june

Mucosal immunity in the bladder
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Urinary tract infections (UTI) are the second most common infection, impacting nearly 50% of all women. Indeed, otherwise healthy, premenopausal women have a significantly greater incidence of urinary tract infection (UTI) than men, yet, conversely, male UTI is more persistent with greater associated morbidity. Additionally, both sexes are at significant risk of reinfection, suggesting that adaptive immune responses to this infection are insufficient. Our group is interested in identifying the mechanisms that govern sex bias and development of immunity in UTI. Our recent work demonstrates that resident macrophages impair the adaptive response, and that IL-17 is a critical player in resolution of infection. We also identified events leading to the development of antigen-specific tissue-resident T cells in the bladder that are necessary and sufficient for protection against recurrent infection. We are now determining how this response can be immunomodulated for improved therapeutics that obviate the need for antibiotics to treat multidrug resistant uropathogens.

Molly Ingersoll, PhD
Pasteur Institute, France

Cancer Immunology
2nd july

Translating immune regulation into patient treatment in human diseases
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In contrast to αβ T cells, γδ T cell activation is MHC-unrestricted and relies on the detection  of various host cell-derived molecules or exogenous pathogens by both TCR and non-TCR receptors. γδ T cells represent the earliest source of IFNγ secretion in the tumor microenvironment and recent transcriptome analyses of human tumors reveal that high γδ T infiltration has the best prognostic value in comparison to other immune subsets. Vγ9Vδ2 T cells are the major subtype of blood γδ T cells and are activated by non-peptidic phosphorylated metabolites, called phosphoantigens (pAgs), produced by transformed or infected cells.

During this presentation we will address 1) the role of these cells as prognostic markers in various hematological and solid tumors ; 2) their mechanismm of action against tumors ; 3) clinical trials in solid tumors and leukemias.

Daniel Olive, MD, PhD
Cancer research center of Marseille (CRCM), France

Bcells/antibodies
23rd april
FIRST WEBINAR SESSION

Functions of two humoral memory populations and their generation mechanisms
→ Read the abstract

The successful establishment of humoral memory response depends on at least two layers of defense. Pre-existing protective antibodies secreted by long-lived plasma cells (LLPCs) act as a first line of defense against reinfection (“constitutive humoral memory”). Previously, a second line of defense in which pathogen-experienced memory B cells are rapidly reactivated to produce antibodies (“reactive humoral memory”), was considered as simply a back-up system for the first line (particularly for re-infection with homologous viruses). By using influenza model system, we found that, in the case of re-infection with similar but different strains of viruses, the constitutive humoral memory (LLPCs) is no more protective, while reactive humoral memory (memory B cells) plays a crucial role. These somewhat differential roles of LLPCs and memory B cells promoted us to look for the generation mechanisms of the two compartments in germinal centers (GCs). We proposed the affinity instruction model, whereby a high-affinity or low-affinity BCR is the primary determinant for LLPC or memory B cell generation, respectively. I will present the experimental data to support this model.    

Tomohiro Kurosaki, MD, PhD
RIKEN Center for Integrative Medical Sciences, Osaka University, Japan

Unveiling the molecular basis of T cell malfunctions and disorders using multi-omics approaches
→ Read the abstract

T cells play a central role in adaptive immunity. Although the T cell antigen receptor (TCR) primarily controls T cell physiology, it does not work in isolation and the signals it triggers are tuned by a multitude of other surface receptors that deliver positive (costimulators) and negative (coinhibitors) informations about the state of activation of antigen-presenting cells (primarily dendritic cells). Therapeutic antibodies (immune-checkpoint inhibitors) blocking coinhibitors have become standard treatment for several malignant conditions, leading to a revival in the study of T cell coinhibition and costimulation. However, we lack a satisfying comprehension of the way T cells integrate inputs from multiple signalling pathways and use inter-pathway crosstalk to make informed decisions. To make sense of the formidable complexity of the signal transduction networks involved in T cell activation and the role played by the different types of dendritic cells in T cell activation, we combined “omic” and mouse genetics. It allowed us to decipher in a time-resolved and quantitative manner the dynamics of the protein signaling complexes (signalosomes) that assemble in primary T cells following physiologic TCR engagement. To further illustrate the interest of multi-omics approaches, I will present recent data generated with several Japanese collaborators and demonstrating how corrupted LAT signalosomes lead to an inflammatory and autoimmune disease recapitulating human IgG4-related disease.

Bernard Malissen, PhD
Marseille-Luminy Immunology center (CIML), France

Organizers
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