Abstract
During our life, we are surrounded by continuous threats from a diverse range of invading pathogens. Our immune system has evolved multiple mechanisms to efficiently deal with these threats so as to prevent them from causing disease. Terminal differentiation of mature B cells into plasma cells (PC) – the antibody (Ab) secreting cells of the immune system – is critical for the generation of protective and long-lived humoral immune responses. Indeed, efficient production of antigen (Ag)-specific Ab by activated B cells underlies the success of most currently available vaccines. The mature B-cell pool is composed of several subsets, distinguished from one according to size, surface marker expression, location, and Ag exposure, and they all have the capacity to differentiate into PCs. For a B-cell to acquire the capacity to produce Abs, it must undergo an extensive differentiation process driven by changes in gene expression. Two broad categories of Ags exist that cause B-cell activation and differentiation: T cell dependent (TD) or T cell independent (TI). In addition to the B-cell subset and nature of the Ag, it is important to consider the cytokine environment that can also influence how B-cell differentiation is achieved. Thus, while many cytokines can induce Ab-secretion by B cells after activation with mimics of TD and TI stimuli in vitro, they can have different efficacies and specificities, and can often preferentially induce production of one particular Ig isotype over another. Here, we will provide an overview of in vitro studies (mouse and human origin) that evaluated the role of different cytokines in inducing the differentiation of distinct B-cell subsets to the PC lineage. We will place particular emphasis on IL-21, which has emerged as the most potent inducer of terminal B-cell differentiation in humans. We will also focus on the role of IL-21 and defects in B-cell function and how these contribute to human immunopathologies such as primary immunodeficiencies and B-cell mediated autoimmune conditions.
Highlights
The humoral arm of the immune system is critical for providing protective antibodies (Abs) against infection pathogens
This differentiation event is in part mediated by T follicular helper (Tfh) cells, a distinct subset of CD4+ T cells characterized by expression of the transcriptional repressor B-cell lymphoma-6 (Bcl-6), the surface markers CXCR5, PD-1, ICOS, and CD40 ligand (CD40L), and production of various cytokines including interleukin-4 (IL-4), IL-10, and IL-21
IL-21 enhanced proliferation of anti-IgM and/or anti-CD40 mAb-stimulated murine B cells and initiated plasma cells (PC) differentiation and class switching, as revealed by increased expression of Syndecan-1 (CD138) and surface IgG1 on these cells [86]. These findings provided strong evidence that IL-21 is likely to achieve its potent effect on humoral immune responses in vivo by acting directly on B cells
Summary
The humoral arm of the immune system is critical for providing protective antibodies (Abs) against infection pathogens. PLASMA CELL FORMATION: THE IMPORTANCE OF T CELLS, CYTOKINES, AND TRANSCRIPTION FACTORS Plasma cells are generated as a result of cognate interactions between Ag-specific B cells, CD4+ T helper cells, and dendritic cells in response to foreign Ags (Figure 1) These interactions can drive B cells to become low-affinity short-lived, predominantly IgMsecreting, plasmablasts that provide an initial wave of protection against invading pathogens. More importantly though, they lead to the formation of germinal centers (GCs), which are specialized structures in the follicles of secondary lymphoid tissues where somatic hypermutation (SHM) of immunoglobulin (Ig) variable region genes and selection of high-affinity B cells occurs. The key transcription factors involved in regulating www.frontiersin.org
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