Revisiting the B-cell compartment in mouse and humans: more than one B-cell subset exists in the marginal zone and beyond.

International audienceABSTRACT: The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories - the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells - plus the detailed description of the main B-cell regulator, FcγRIIb, and the function of CD40+ antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express "Pathogen Recognition Receptors" such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology

NK cell receptors: evolution and diversity

Natural Killer cell functions are regulated by combinations of activating and inhibitory receptors, derived from a number of different gene families. This review focuses on receptors for MHC class I, which include the killer cell immunoglobulin-like receptors (KIR) and the CD94:NKG2 family of receptors. In particular the KIR are diverse and rapidly co-evolving with their classical MHC class I ligands. Thus NK cells are part of the innate immune system that are continuing to adapt to the challenges of pathogens

Impact de BAFF et des protéines gp120 du VIH-1 sur le trafic des lymphocytes B humains (Mécanismes d'action et effecteurs cibles)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

B-Cell-Activating Factor and the B-Cell Compartment in HIV/SIV Infection

With the goal to design effective HIV vaccines, intensive studies focused on broadly neutralizing antibodies, which arise in a fraction of HIV-infected people. Apart from identifying new vulnerability sites in the viral envelope proteins, these studies have shown that a fraction of these antibodies are produced by self/poly-reactive B-cells. These findings prompted us to revisit the B-cell differentiation and selection process during HIV/SIV infection and to consider B-cells as active players possibly shaping the helper T-cell program within germinal centers (GCs). In this context, we paid a particular attention to B-cell-activating factor (BAFF), a key cytokine in B-cell development and immune response that is overproduced during HIV/SIV infection. As it does in autoimmune diseases, BAFF excess might contribute to the abnormal rescue of self-reactive B-cells at several checkpoints of the B-cell development and impair memory B-cell generation and functions. In this review, we first point out what is known about the functions of BAFF/a proliferation-inducing ligand and their receptors [B-cell maturation, transmembrane activator and CAML interactor (TACI), and BAFF-R], in physiological and pathophysiological settings, in mice and humans. In particular, we highlight recent results on the previously underappreciated regulatory functions of TACI and on the highly regulated production of soluble TACI and BAFF-R that act as decoy receptors. In light of recent data on BAFF, TACI, and BAFF-R, we then revisit the altered phenotypes and functions of B-cell subsets during the acute and chronic phase of HIV/SIV infection. Given the atypical phenotype and reduced functions of memory B-cells in HIV/SIV infection, we particularly discuss the GC reaction, a key checkpoint where self-reactive B-cells are eliminated and pathogen-specific memory B-cells and plasmablasts/cells are generated in physiological settings. Through its capacity to differentially bind and process BAFF-R and TACI on GC B-cells and possibly on follicular helper T-cells, BAFF appears as a key regulator of the physiological GC reaction. Its local excess during HIV/SIV infection could play a key role in B-cell dysregulations

Corruption of Human Follicular B-Lymphocyte Trafficking by a B-Cell Superantigen

Protein A (SpA) of Staphylococcus aureus is known to target the paratope of immunoglobulins expressing VH3 genes, and to delete marginal zone B cells and B-1a in vivo. We have discovered that SpA endows S. aureus with the potential to subvert B-cell trafficking in the host. We found that SpA, whose Fc-binding site has been inactivated, binds essentially to naïve B cells and induces a long-lasting decrease in CXCR4 expression and in B-cell chemotaxis to CXCL12. Competition experiments indicated that SpA does not interfere with binding of CXCR4 ligands and does not directly bind to CXCR4. This conclusion is strongly supported by the inability of SpA to modulate clathrin-mediated CXCR4 internalization, which contrasts with the potent effect of anti-immunoglobin M (IgM) antibodies. Microscopy and biochemical experiments confirmed that SpA binds to the surface IgM/IgD complex and induces its clathrin-dependent internalization. Concomitantly, the SpA-induced signaling leads to protein kinase C–dependent CXCR4 downmodulation, suggesting that SpA impairs the recycling of CXCR4, a postclathrin process that leads to either degradation into lysozomes or de novo expression at the cell surface. In addition to providing novel insight into disruption of B-cell trafficking by an infectious agent, our findings may have therapeutic implications. Because CXCR4 has been associated with cancer metastasis and with certain autoimmune diseases, SpA behaves as an evolutionary tailored highly specific, chemokine receptor inhibitor that may have value in addition to conventional cytotoxic therapy in patients with various malignancies and immune-mediated diseases

Revisiting the B-cell compartment in mouse and humans: more than one B-cell subset exists in the marginal zone and beyond

Abstract The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories — the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells — plus the detailed description of the main B-cell regulator, FcγRIIb, and the function of CD40+ antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express “Pathogen Recognition Receptors” such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology.</p