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
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
