Leukemia (2016) 30, 2283–2292 © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0887-6924/16 www.nature.com/leu REVIEW Human memory B cells M Seifert and R Küppers A key feature of the adaptive immune system is the generation of memory B and T cells and long-lived plasma cells, providing protective immunity against recurring infectious agents. Memory B cells are generated in germinal center (GC) reactions in the course of T cell-dependent immune responses and are distinguished from naive B cells by an increased lifespan, faster and stronger response to stimulation and expression of somatically mutated and affinity matured immunoglobulin (Ig) genes. Approximately 40% of human B cells in adults are memory B cells, and several subsets were identified. Besides IgG+ and IgA+ memory B cells, ∼ 50% of peripheral blood memory B cells express IgM with or without IgD. Further smaller subpopulations have additionally been described. These various subsets share typical memory B cell features, but likely also fulfill distinct functions. IgM memory B cells appear to have the propensity for refined adaptation upon restimulation in additional GC reactions, whereas reactivated IgG B cells rather differentiate directly into plasma cells. The human memory B-cell pool is characterized by (sometimes amazingly large) clonal expansions, often showing extensive intraclonal IgV gene diversity. Moreover, memory B-cell clones are frequently composed of members of various subsets, showing that from a single GC B-cell clone a variety of memory B cells with distinct functions is generated. Thus, the human memory B-cell compartment is highly diverse and flexible. Several B-cell malignancies display features suggesting a derivation from memory B cells. This includes a subset of chronic lymphocytic leukemia, hairy cell leukemia and marginal zone lymphomas. The exposure of memory B cells to oncogenic events during their generation in the GC, the longevity of these B cells and the ease to activate them may be key determinants for their malignant transformation. Leukemia (2016) 30, 2283–2292; doi:10.1038/leu.2016.226 INTRODUCTION GENERATION OF B CELLS The success of vaccination in eradicating life-threatening infec- Throughout life, B cells are generated from lymphoid precursors. tions is often considered as the most important medical break- B-cell generation occurs in the bone marrow in a tightly regulated through in the past century. The immunological memory that is process, with stepwise recombination of V, (D) and J gene generated upon vaccination rests on our adaptive immune system segments coding for the variable (V) region of the immunoglo- 1 and its two key cell types, B and T lymphocytes. Although innate bulin (Ig) heavy and light chains. If a B cell succeeds in producing immunity can cope with most infectious insults, the severe a functional, non-autoreactive BCR, it differentiates into a mature, diseases that result from deficiencies in the function of B and/or naive B cell. These cells express the BCR as IgM and IgD molecules, recirculate through the body and account for ∼ 50% of B cells in T cells demonstrate the important role of the adaptive immune 2 system. The key to adaptive immunity is the expression of highly adults. As multiple V, D and J gene segments are available for V diverse antigen receptors on T and B lymphocytes, the T-cell (D)J recombination, and as additional variability is generated at the joining sites, each newly generated B cell is equipped with a receptor and the B-cell receptor (BCR), respectively, that enable a unique BCR that hence represents a clonal marker. In this way, a highly specific response against all types of foreign antigens. highly diverse primary repertoire of naive B cells is generated.1 A further hallmark of the adaptive immune system is the generation of immune memory. This is provided by memory lymphocytes that are generated in immune responses against GENERATION OF MEMORY B CELLS IN THE GERMINAL CENTER specific antigens, are long-lived and provide an enhanced and REACTION improved immune reaction upon reencounter of cognate antigen. Upon strong BCR stimulation, B cells can proliferate and Thereby, memory lymphocytes protect the organism from differentiate into plasma cells (PCs) without the need for T-cell diseases caused by reinfection with the same or similar infectious support. Such T cell-independent (TI) immune responses generate agents, sometimes for decades. PCs producing antibodies of low affinity and typically do not give In recent years, considerable progress has been made in our rise to memory B cells.3 If an antigen can be presented to T helper understanding of the generation and diversity of memory B cells, (Th) cells via major histocompatibility complex class II molecules, a their distinct subsets and functions. However, several aspects of T cell-dependent (TD) humoral immune response is initiated. this topic are still unresolved or debated. We present here an B cells are activated in the periphery and migrate into secondary overview on human memory B cells, addressing these issues and lymphoid tissues, or are activated locally by floating antigen or we also consider the pathogenesis of memory B cell-derived immune complexes, presented by dendritic cells. The activated B malignancies. cells meet antigen-specific Th cells at the border of the T-cell zone Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen, Germany. Correspondence: Professor R Küppers, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Virchowstraße 173, 45122 Essen, Germany. E-mail: [email protected] Received 24 May 2016; revised 29 June 2016; accepted 26 July 2016; accepted article preview online 8 August 2016; advance online publication, 26 August 2016 Human memory B cells M Seifert and R Küppers 2284 and B cell follicle.4 The cognate B-cell–Th cell interaction leads to a undergoes class-switch recombination. In this process, the further stimulation of both types of cells in primary focus originally expressed Cμ and Cδ genes are replaced by one of reactions, where they proliferate, and short-lived, mostly IgM the 3′ located CH genes, Cγ1-4, Cα1 and 2 or Cε. These encode secreting, PCs are generated.4 heavy chains that equip secreted antibodies with distinct effector A fraction of the activated lymphocytes migrates into B-cell functions.1 follicles and seeds germinal center (GC) reactions.1,5 These GC Induction of the PC program is regulated by the transcription founder B cells upregulate BCL6, the master regulator of the factors PRDM1, IRF4 and XBP1.10 PRDM1 and IRF4 both suppress GC program, already before GC entry and vigorously proliferate BCL6, and thereby the GC B-cell program, and induce together (Figure 1).6 Proliferation in the GC is accompanied by somatic with XBP1 the expression of PC-specific genes.10 Notably, class hypermutation (SHM) that introduces mutations at a rate switching can also bias GC B cells toward PC differentiation.11 In − − of 10 3–10 4/bp/cell division into the rearranged IgV genes. contrast, the regulation of memory B-cell differentiation is poorly SHM requires strong transcriptional activity of the IgV genes.7 SHM understood. The transcription factor nuclear factor-κB, which is not only targets the IgV genes, but with lower frequency also induced in centrocytes by CD40 and BCR triggering and can some non-Ig genes transcribed in GC B cells, including BCL6.8 downregulate BCL6, is involved in this process,12 and interleukin- Despite some preferences, somatic mutations occur in principle 24 can also enhance memory B-cell formation.13 In mice, the randomly downstream from the IgV promoter over a region of transcription factor Bach2 plays a key role in selecting GC B cells ∼ 1 kb. Most mutations will cause an amino acid exchange.7 The with intermediate affinity into the memory B-cell compartment.14 vast majority of such replacement mutations will be disadvanta- Plasmablasts may migrate into specialized niches in the bone geous, for example, if reducing BCR affinity. Hence, most marrow, where they terminally differentiate into long-lived PCs, progenies of a somatically mutating B-cell clone represent secreting large amounts of high-affinity antibody over extended unfavorable variants that are eliminated by apoptosis.1 Only if a time periods.10 Memory B cells circulate through the body as BCR with improved affinity is expressed, the respective cell is resting lymphocytes until reactivation. Whereas the established positively selected through cognate interaction between GC high-affinity antibody titer in lymph and blood represents a direct B cells and GC Th cells.9 This selection takes place in the light and continuously ongoing defense mechanism provided by PCs, zone of the GC, where GC B cells show little proliferative activity memory B cells require restimulation to provide enhanced and (centrocytes), whereas mutating and proliferating GC B cells improved immune responses. (centroblasts) are mostly restricted to the dark zone. GC B cells A vast majority of memory B cells are generated in GC reactions typically acquire one or a few mutations before migrating to the (Figure 1). However, in the mouse, some memory B cells are light zone. Positively selected centrocytes either return to the dark generated upon T-cell stimulation already before GC passage. zone for further proliferation and mutation or differentiate into These cells are partly class switched, carry unmutated IgV PCs or memory B cells.5 In the light zone, a fraction of GC B cells genes15,16 and likely represent progeny of the primary focus Figure 1. Memory B-cell generation in the GC. (Left) After initial encounter of antigen-specific B and T cells at the border of T-cell zone and B-cell follicle (primary focus reaction), activated B and T cells migrate into the follicles and initiate GC reactions.