Molecular programming of B cell memory.
ABSTRACT The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information - resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes - has reshaped the conceptual landscape surrounding the generation of memory B cells. In this Review, we integrate this new information about each phase of antigen-specific B cell development to describe the newly unravelled molecular dynamics of memory B cell programming.
- SourceAvailable from: Katerina Hatzi[Show abstract] [Hide abstract]
ABSTRACT: To understand how the Bcl6 transcriptional repressor functions in the immune system, we disrupted its RD2 repression domain in mice. Bcl6RD2(MUT) mice exhibit a complete loss of germinal center (GC) formation but retain normal extrafollicular responses. Bcl6RD2(MUT) antigen-engaged B cells migrate to the interfollicular zone and interact with cognate T helper cells. However, these cells fail to complete early GC-commitment differentiation and coalesce as nascent GC aggregates. Bcl6 directly binds and represses trafficking receptors S1pr1 and Gpr183 by recruiting Hdac2 through the RD2 domain. Deregulation of these genes impairs B cell migration and may contribute to GC failure in Bcl6RD2(MUT) mice. The development of functional GC-TFH cells was partially impaired in Bcl6RD2(MUT) mice. In contrast to Bcl6(-/-) mice, Bcl6RD2(MUT) animals experience no inflammatory disease or macrophage deregulation. These results reveal an essential role for RD2 repression in early GC commitment and striking biochemical specificity in Bcl6 control of humoral and innate immune-cell phenotypes.Cell reports. 08/2014;
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ABSTRACT: Germinal centers (GCs) are specialized environments in which B cells mutate their BCR to identify new Abs with high affinity to a challenging Ag. B cells are selected in an evolutionary process of multiple rounds of mutation and selection. In the past decade, mechanisms of B cell migration, division, mutation, selection, and final differentiation have been extensively studied. Thereby, modulations of these mechanisms either optimize the quality, in terms of affinity, or the quantity of generated Abs, but never both, leading to an unclear effect on the overall efficiency of the Ab response. In this article, we predict with mathematical models that an affinity-dependent number of GC B cell divisions overcomes the dichotomy of quality and quantity, and has to be considered as a good target for immune interventions, in particular, in the elderly population with poor GC responses.Journal of immunology (Baltimore, Md. : 1950). 10/2014;
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ABSTRACT: BACKGROUND: Antibody responses to hepatitis C virus (HCV) occur delayed and overly decline after viral clearance indicating that the B-cell response to HCV is abnormal. Virus-specific memory B-cells have recently been found in infected individuals, but the viral exposure requirements for the generation of these cells is unknown. OBJECTIVES: The primary goal of this study was to quantify and compare the HCV-specific memory B-cell response between chronic and resolved HCV-infected individuals. A secondary goal was to examine if HIV-specific memory B-cell responses are maintained during HCV co-infection. STUDY DESIGN: HCV core protein- and HIV-specific memory B-cell responses were examined in HIV/HCV-infected individuals treated 4-30 weeks after HCV diagnosis. Memory B-cell frequencies were compared between chronically and transiently infected individuals. RESULTS: Chronically infected individuals had vigorous HCV-specific memory B-cell responses and antibodies, whereas subjects with transient viremia showed low or undetectable virus-specific B-cell responses. In addition, chronically HIV/HCV-infected subjects had robust HIV-specific memory B-cell responses. CONCLUSIONS: Whereas chronic HCV infection induces virus-specific antibodies and memory B-cells, transient infection in individuals with sustained viral response to therapy does not stimulate a durable HCV-specific B-cell response indicating that the formation of long-lived virus-specific B-cells is suppressed in the early phase of infection. This may contribute to the inability to spontaneously clear HCV infection.Journal of Clinical Virology 02/2014; 59(4):218-222. · 3.47 Impact Factor