Effector and memory B lymphocytes
RESEARCH FOCUS: B CELL IMMUNOLOGY
Many challenges remain in understanding the regulation of B cell responses at homeostasis or in the context of infection and human pathologies (antibody-mediated graft rejection, autoimmunity, lymphoma). Our goal is to decipher the molecular and cellular mechanisms underlying normal and pathogenic B cell responses. We use a multilevel approach that can be summarized as follows:
1- The immunological synapse. Once they have received an antigen signal, B lymphocytes will successively create synapses with different cell types along their way to differentiate into memory or effector cells. We contend that ubiquitous cytokines such as TGFβ will have differential outcomes on B cell responses depending on the B cell cellular partner. This research topic explores the molecular and cellular signals that govern B cell behavior and function upon encounter with their successive cellular partners, in particular in the context of mucosal immune responses. It is directed by Helena Paidassi (CR CNRS).
2- Lymphocyte populations. One of the key notions that emerged during the past 10 years is that B (but also T) cell populations are diverse and complex. It is admitted for example that the memory B cell compartment is multilayered and that this evolutionary trait has been selected to optimally protect the host facing the structural diversity of the antigenic world, mutating pathogens, their route of entry etc…In this part of the project we focus on: i) deciphering the complexity of the memory B and memory plasma cell compartments, ii) understanding the biological roles of some of these memory subsets and iii) determining whether the anatomy of the memory B cell compartment can be manipulated with vaccination tools to build a sort of “tailored” memory. This research topic is directed by Thierry Defrance (DR INSERM).
3- The whole organism. A lot of our knowledge on B cell responses originates from studies conducted with model antigens (often hapten-carrier couples) that preclude examination of how vaccination and building of immune memory impact on integrity of the host. One of the pathophysiological situations in which the immune system is put to the test is organ allograft. We focus on chronic graft rejection, which is mediated by the Ab response and remains the cause of organ rejection despite the immunosuppressive treatments. In this part of the project, we combine fundamental studies to dissect molecular and cellular mechanisms of immune cell networks in vitro and in animal models, with translational studies of immune pathologies in Humans. Through this transversal approach, we aim at better understanding humoral immunity and the pathophysiology of B cell-mediated diseases, with the ultimate goal to develop new therapeutic strategies: reduction of antibody responses in transplant patients, innovating vaccination strategies for infectious diseases or antigen-specific responses for biotherapies. This research topic is directed by Olivier Thaunat (PU-PH).
TOOLS AND EXPERTISE
Multiple models of genetically-modified mice, analysis of antigen-specific B cell responses in the mouse (Elisa, Elispot, flow cytometry), bacterial infection models (S. pneumoniae, S. aureus), murine models of organ transplantation, mucosal immune responses, high dimensional phenotypic analysis by multiparameter flow and mass cytometry, epigenetic analysis (ATAC-seq, ChIP-seq), preparation of synthetic particulate antigens for immunotherapy and vaccination, access to patient cohorts.
– Immunoregulatory role of CD31 shapes the compartmentalization of rejection lesions in solid organ transplantation (ANR and CENTAURE foundation funding, PI: O. Thaunat)
– Asymmetric segregation of antigen upon B cell division and diversification of clonal progeny (PI: O. Thaunat)
– Influence of vaccine formulation on the anatomy of the B and TFH memory compartments (MEMO-SIGN project, ANR funding, PI: T. Defrance).
– Exploration of the biological function of a BCR-expressing atypical plasma cell population (PI: T. Defrance).
– High-dimensional phenotypical analysis of the residual healthy B cell compartment of B-CLL patients (La ligue contre le Cancer funding, PI: T. Defrance).
– Epigenetic regulation of αvβ8 integrin expression (PI: H. Paidassi)
– Fine-tuning of the germinal center reaction by TGFβ and αvβ8 integrin (PI: H. Paidassi)
RECENT SCIENTIFIC ACHIEVEMENTS
– Identification of an atypical plasma cell subset expressing a functional BCR -retaining the ability to sense Ag
– Role of vascular sequestration for protection of pancreatic islet grafts from antibody-mediated rejection
– Identification of a novel type of rejection mediated by innate effectors (patent # EP17306154)
– Development of biofunctionalized nanoparticles and uses thereof in adoptive cell therapy (patent # EP2016/072983)
– Development of synthetic particulate Ag allowing to use generate Ag-specific TFH cells
– Mechanisms of regulation of β8 integrin expression in dendritic cells for orchestration of TGFβ-dependent mucosal immune responses