Translating transitions - how to decipher peripheral human B cell development

Abstract

During the last two decades our understanding of human B cell differentiation has developed considerably. Our understanding of the human B cell compartment has advanced from a point where essentially all assays were based on the presence or not of class-switched antibodies to a level where a substantial diversity is appreciated among the cells involved. Several consecutive transitional stages that newly formed IgM expressing B cells go through after they leave the bone marrow, but before they are fully mature, have been described, and a significant complexity is also acknowledged within the IgM expressing and class-switched memory B cell compartments. It is possible to isolate plasma blasts in blood to follow the formation of plasma cells during immune responses, and the importance and uniqueness of the mucosal IgA system is now much more appreciated. Current data suggest the presence of at least one lineage of human innate-like B cells akin to B1 and/or marginal zone B cells in mice. In addition, regulatory B cells with the ability to produce IL-10 have been identified. Clinically, B cell depletion therapy is used for a broad range of conditions. The ability to define different human B cell subtypes using flow cytometry has therefore started to come into clinical use, but as our understanding of human B cell development further progresses, B cell subtype analysis will be of increasing importance in diagnosis, to measure the effect of immune therapy and to understand the underlying causes for diseases. In this review the diversity of human B cells will be discussed, with special focus on current data regarding their phenotypes and functions.

Fig. 1. Antigen independent and dependent B lymphoid development.

B cell development can be divided into an antigen independent phase (A) that generates vast diversity while still avoiding the formation of autoreactive cells and an antigen dependent phase (B) that allows for the activation, expansion and differentiation of antigen-specific B cells into effector and memory cells. A: During the antigen independent phase, hematopoietic stem cells in the bone marrow are selected to become B cells. During the pre- and pro-B cell stages the cells create a functional heavy chain gene through random recombination of V, D and J segments, a process that is monitored through pairing of the heavy chain gene with surrogate light chains (red). When a functional heavy chain gene has formed, the cell creates functional light chain genes through recombination of V and J segments, first in the κ light chain locus and then, if κ is unsuccessful, the λ light chain locus. When productive rearrangements have been achieved for both a heavy and a light chain, the mature antigen receptor (the B cell receptor, BCR) of the IgM class as is expressed on the cell surface on immature B cell. After the immature B cell leave the bone marrow and enter into blood stream and the peripheral lymphoid organs, it goes through a transitional stage before becoming a fully mature naïve B cell. If the cell encounters antigen that bind to the BCR on the cell surface during the immature or transitional stages, the cell will be deleted, a mechanism that hinders autoreactive B cells to reach the mature stage. B: An external antigen will be recognized by BCRs on a small number of mature naïve B cells that will be activated. This leads to that the B cells start to proliferate, take up antigen and present peptides derived from it on MHC II molecules on the cell surface. If the B cells encounter T cells that recognize peptides from the same antigen presented on MHC II through their T cell receptors (TCR) a T dependent (T dep) response is initiated. B cells will revive additional signals from the T cells, in particular from secreted cytokines and CD40L biding to CD40, and proliferating cells will enter B cell follicles to form germinal centers of rapidly proliferating cells. Here, the B cells change antibody class to other classes than IgM (i.e. IgG, IgE and IgA) through class switch recombination. Furthermore, the antigen binding V regions of the antibody genes goes through targeted somatic hypermutation followed by a selection for cells that express high affinity BCR, a process known as affinity maturation. Subsequently, cells leave the germinal center to form long-lived class-switched memory B cells that can rapidly respond if we reencounter the same antigen and long-lived plasma cells that home to bone marrow and produce secreted antigen-specific class-switched antibodies for extended periods. B cells that recognize antigens in the absence of T cell interactions (T independent responses; T indep) and some B cells that respond to T dependent antigen swill form extrafollicular foci and form relatively short-lived plasma cells secreting IgM that are maintained in peripheral lymphoid organs.

Fig. 2. Transitional B cells in mouse and humans.

B cells go through several stages after leaving the bone marrow but before becoming fully mature. During these stages, self-reactive cells are depleted due to interactions with self-antigens and are also selected into different lineages. The different stages can be defined based on expression of cell surface antigens. Changes important for defining different stages have been marked in bold. A: Several stages that mouse transitional T cells go through after leaving the bone marrow have been defined based on cell surface markers and transfer experiments. T1 cells in spleen are similar to immature B cells in the bone marrow. CD23 and IgD are upregulated when the cells become T2 cells, and T1/T2 cells are also precursors to MZ B cells. A T3 stage has also been defined. T3 cells were first suggested to be a pre-stage to mature follicular cells, but later analysis revealed that this population may be enriched for autoreactive cells and may be targeted for deletion through apoptosis due to interactions with self antigens. Cell phenotypes adopted from Allman and Pillai, 2008^[8] in which the relationship between different transitional and more mature stages is discussed. B: Also in humans several transitional stages have been defined, going from immature B cells leaving bone marrow to naïve follicular B cells and circulating MZ-like/B1-like lineage B cells. Although transitional cells are termed T1, T2 and T3 in both humans and mice, there is not necessarily a direct correlation between them. Many expression changes during human transitional development are continuous, making it hard to set clear gates between different populations. The T3 population can be divided into two (T3 and T3′) based on expression of the CD45RB^MEM55glyco-epitope and IgM, and CD45RB^MEM55/IgM^high T3 cells appear to be precursors to innate MZ/B1-like B cells. Cells with T1, T2 or T3 phenotypes have been identified both in peripheral blood and in the bone marrow. It is unknown if this is due to circulation of cells or if some cells go through these developmental stages within the bone marrow before release. Cell phenotypes are adopted from Bemark et al., 2012^[17].

Fig. 3. B cell lineages.

Different lineages of B cells in mice, and data in humans support that this is also true in humans. A: Three mature lineages of B cells have been defined in mice – follicular, marginal zone and B1 B cells. Follicular and marginal zone B cells share early maturation stages and are formed all through life. After MZ B cells receive a yet undefined cue they interact via Notch-mediated signals with cells in the spleen to become mature MZ B cells. B1 cells form, at least partly, from distinct stem cells in bone marrow and fetal spleen. Furthermore, B1 cells formed during early life form a self-renewing pool of cells in peritoneal cavities that does not depend on bone marrow production of cells for maintenance. B: The situation in humans is less clear, but several groups have described cell populations with similarities to MZ and/or B1 cells in lymphoid organs and blood. These express high levels of IgM, CD27 and the CD45RB^MEM55glyco-epitope. It is not known if they form from specific stem cells or transitional cells, but a cell population with the ability to differentiate into this lineage through Notch-mediated signals similar to the situation in mouse spleen was recently defined in the human spleen^[123].