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Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage.

Moens L, Tangye SG - Front Immunol (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Immunodeficiency Group, Immunology Research Program, Garvan Institute of Medical Research , Darlinghurst, NSW , Australia.

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.

No MeSH data available.


Related in: MedlinePlus

T cell dependent B-cell differentiation. Following the receipt of signals provided by the microenvironment [e.g., Ag, CD4+ T (Tfh) cells, DC], naïve B cells undergo activation and can initially differentiate into either extrafollicular short-lived Ab-secreting plasma cells (secreting predominantly IgM), or can seed a germinal center (GC). Within GCs, B cells undergo somatic hypermutation of their Ig V region genes and only those B cells with the highest affinity are selected to then differentiate into long-lived memory B cells or plasma cells that are capable of secreting a variety of Ig isotypes, including the switched isotypes IgG, IgA, and IgE. The outcome of the GC reaction is heavily influenced by Tfh cells, especially those within the GC itself. These cells are not depicted on the figure but they contribute greatly at this stage of B-cell differentiation. Following re-encounter with the initiating Ag, memory B cells rapidly differentiate into plasma cells. The differentiation of naïve B cells to these distinct effector fates is controlled by the balanced expression and regulated function of various transcription factors, including (but not exclusively) PAX5, BCL-6, BLIMP-1, XBP-1, and IRF4.
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Figure 1: T cell dependent B-cell differentiation. Following the receipt of signals provided by the microenvironment [e.g., Ag, CD4+ T (Tfh) cells, DC], naïve B cells undergo activation and can initially differentiate into either extrafollicular short-lived Ab-secreting plasma cells (secreting predominantly IgM), or can seed a germinal center (GC). Within GCs, B cells undergo somatic hypermutation of their Ig V region genes and only those B cells with the highest affinity are selected to then differentiate into long-lived memory B cells or plasma cells that are capable of secreting a variety of Ig isotypes, including the switched isotypes IgG, IgA, and IgE. The outcome of the GC reaction is heavily influenced by Tfh cells, especially those within the GC itself. These cells are not depicted on the figure but they contribute greatly at this stage of B-cell differentiation. Following re-encounter with the initiating Ag, memory B cells rapidly differentiate into plasma cells. The differentiation of naïve B cells to these distinct effector fates is controlled by the balanced expression and regulated function of various transcription factors, including (but not exclusively) PAX5, BCL-6, BLIMP-1, XBP-1, and IRF4.

Mentions: 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 IgM-secreting, plasmablasts that provide an initial wave of protection against invading pathogens. More importantly though, they also 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. These selected high-affinity variants can then differentiate into long-lived memory B cells or PCs (2, 3) (Figure 1). 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. Tfh cells localize to follicles and GCs – where they are termed “GC Tfh cells” – where they can interact with B cells and instruct their maturation into memory cells or PCs (4–6).


Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage.

Moens L, Tangye SG - Front Immunol (2014)

T cell dependent B-cell differentiation. Following the receipt of signals provided by the microenvironment [e.g., Ag, CD4+ T (Tfh) cells, DC], naïve B cells undergo activation and can initially differentiate into either extrafollicular short-lived Ab-secreting plasma cells (secreting predominantly IgM), or can seed a germinal center (GC). Within GCs, B cells undergo somatic hypermutation of their Ig V region genes and only those B cells with the highest affinity are selected to then differentiate into long-lived memory B cells or plasma cells that are capable of secreting a variety of Ig isotypes, including the switched isotypes IgG, IgA, and IgE. The outcome of the GC reaction is heavily influenced by Tfh cells, especially those within the GC itself. These cells are not depicted on the figure but they contribute greatly at this stage of B-cell differentiation. Following re-encounter with the initiating Ag, memory B cells rapidly differentiate into plasma cells. The differentiation of naïve B cells to these distinct effector fates is controlled by the balanced expression and regulated function of various transcription factors, including (but not exclusively) PAX5, BCL-6, BLIMP-1, XBP-1, and IRF4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927127&req=5

Figure 1: T cell dependent B-cell differentiation. Following the receipt of signals provided by the microenvironment [e.g., Ag, CD4+ T (Tfh) cells, DC], naïve B cells undergo activation and can initially differentiate into either extrafollicular short-lived Ab-secreting plasma cells (secreting predominantly IgM), or can seed a germinal center (GC). Within GCs, B cells undergo somatic hypermutation of their Ig V region genes and only those B cells with the highest affinity are selected to then differentiate into long-lived memory B cells or plasma cells that are capable of secreting a variety of Ig isotypes, including the switched isotypes IgG, IgA, and IgE. The outcome of the GC reaction is heavily influenced by Tfh cells, especially those within the GC itself. These cells are not depicted on the figure but they contribute greatly at this stage of B-cell differentiation. Following re-encounter with the initiating Ag, memory B cells rapidly differentiate into plasma cells. The differentiation of naïve B cells to these distinct effector fates is controlled by the balanced expression and regulated function of various transcription factors, including (but not exclusively) PAX5, BCL-6, BLIMP-1, XBP-1, and IRF4.
Mentions: 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 IgM-secreting, plasmablasts that provide an initial wave of protection against invading pathogens. More importantly though, they also 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. These selected high-affinity variants can then differentiate into long-lived memory B cells or PCs (2, 3) (Figure 1). 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. Tfh cells localize to follicles and GCs – where they are termed “GC Tfh cells” – where they can interact with B cells and instruct their maturation into memory cells or PCs (4–6).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Immunodeficiency Group, Immunology Research Program, Garvan Institute of Medical Research , Darlinghurst, NSW , Australia.

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.

No MeSH data available.


Related in: MedlinePlus