Memory B cells: Effectors of long‐lived immune responses

Abstract

Immunological memory is the phenomenon whereby B and T cells have the unique ability to respond with heightened kinetics and efficacy to subsequent encounter with Ag relative to the initial exposure. In this review, we examine recent developments in the phenotypic characterisation of memory B cells, with an emphasis on the definition and functional properties of memory B-cell subsets in humans. Gene expression differences are also considered in light of the unique functional and survival properties of memory B cells, and mutations that alter memory formation and function are also examined. Finally, we consider recent advances in the understanding of germinal center B-cell differentiation through analysis of transcription factor networks operating in these B cells. Key words: B cells . Cell differentiation . Memory cells IntroductionThe ability of the immune system to ''remember'' previous encounters with pathogens, and to respond with heightened kinetics and efficacy compared with the initial exposure, is a defining feature of the adaptive immune response of higher vertebrates. The contribution of B cells to immunological memory encompasses two distinct populations of cells that are generated during primary immune responses, long-lived plasma cells (PC), which continue to secrete high levels of neutralising Ig for protracted periods of time well after Ag clearance, and memory B cells, which can rapidly proliferate and differentiate into PC following recurrent exposure to the initial immunising Ag, thereby simultaneously increasing the precursor frequency of Ag-specific memory B cells and enriching the pool of Ag-specific Ig [1][2][3][4]. The ability of naïve B cells to differentiate into memory and PC underlies the success of most -if not all -vaccines currently in use. Despite this, and the fact that we have known about the phenomenon of humoral immunity for centuries, we still do not have a thorough understanding of the biology of memory B cells. Here, we will highlight recent advances, and outstanding questions, in elucidating some of the critical aspects underlying the generation, function and maintenance of memory B cells. Development of serological memory is dependent on germinal centresFollowing initial interactions between protein Ag, naïve B cells and other cells within the lymphoid tissue microenvironment such as CD4 1 T cells, macrophages and DC, the Ag-specific naïve B cells then undergo one of two fates: some of them rapidly differentiate into short-lived PC, which provide a first wave of defence against the invading pathogen, while others migrate to the B-cell follicle and seed a germinal centre (GC) [1][2][3][4][5]. Within GC several cardinal molecular processes necessary for the evolution of long-lived serological immunity take place: somatic hypermutation (SHM) and class switch recombination (CSR) of the Ig V and C region genes, respectively, expressed and secreted [5,8,10,[19][20][21][22][23][24][25][26]. Although these analyses are largely restricted to in vitro experiments, they yielded impo...

Antigen-specific antibody responses in B-1a and their relationship to natural immunity

“…Furthermore, anti-FtL B-1a disappear from the spleen within 1 wk of immunization (19), clearly before the time when GC usually starts developing (27)(28)(29)(30). Finally, B-cell lymphoma 6 (BCL6) up-regulation, a hallmark for GC B cells (26,31,32), is not detected on anti-FtL B-1a (Fig. 2B).…”

Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

“…Several studies have shown that mutated or class-switched Igs can be found among CD27 Ϫ B cells. 7,8 The induction of IgG-secreting cells from within the pool of CD27 Ϫ B cells was first shown by Elispot, although levels were approximately 10-fold lower compared with CD27 ϩ counterparts, and it is possible that class-switching had been induced in vitro. 9 More recently, IgG ϩ /CD27 Ϫ B cells were identified and characterized by more direct methods that revealed a level of SHM that was higher than in IgG Ϫ /CD27 Ϫ but lower than in IgG ϩ /CD27 ϩ B cells.…”

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

“…In fact, several factors could be influencing the GCpromoting effect. There is established and emerging data to suggest that CD40, ICOS, IL-21, programmed cell death-1, CD95, IFN regulatory factor 4, and Bcl-6 are among the factors that critically affect the GC reaction (75)(76)(77). Also, enhanced production of BAFF or a proliferation-inducing ligand could upregulate the GC reaction (78).…”