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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

Cytokine-induced differentiation of human B cells in vitro: requirement for IL-21 signaling in vivo. In vitro studies demonstrated that human B cells could undergo events such as Ig class switching and differentiation to become Ig-secreting cells following stimulation with a diverse range of cytokines. However, analysis of individuals with hypomorphic mutations in genes encoding STAT3, γc (IL2RG), JAK3, or IL-21R have revealed that this pathway – activated by IL-21 – is critical for the generation of memory B cells and the establishment of Ag-specific Abs in vivo. Thus, although cytokines such as IL-4, IL-13, IL-10, and BAFF/APRIL are strong B-cell growth and differentiation factors, their function is insufficient to compensate for impaired IL-21/IL-21R signaling in vivo in the setting of generating robust, long-lived Ag-specific Ab, and memory responses. Consequently, IL-21-mediated B-cell activation is a necessary and sufficient step in the generation of protective long-lived humoral immune responses in humans.
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Figure 2: Cytokine-induced differentiation of human B cells in vitro: requirement for IL-21 signaling in vivo. In vitro studies demonstrated that human B cells could undergo events such as Ig class switching and differentiation to become Ig-secreting cells following stimulation with a diverse range of cytokines. However, analysis of individuals with hypomorphic mutations in genes encoding STAT3, γc (IL2RG), JAK3, or IL-21R have revealed that this pathway – activated by IL-21 – is critical for the generation of memory B cells and the establishment of Ag-specific Abs in vivo. Thus, although cytokines such as IL-4, IL-13, IL-10, and BAFF/APRIL are strong B-cell growth and differentiation factors, their function is insufficient to compensate for impaired IL-21/IL-21R signaling in vivo in the setting of generating robust, long-lived Ag-specific Ab, and memory responses. Consequently, IL-21-mediated B-cell activation is a necessary and sufficient step in the generation of protective long-lived humoral immune responses in humans.

Mentions: The molecular revolution of the 1980s saw the cloning and characterization of several cytokines – IL-2, IL-4, IL-5, IL-6, IFNs – which had B-cell growth and differentiation capacity (Table 1). This continued into the 1990s with the discovery of IL-10, IL-12, IL-13, IL-15, TNFα, BAFF, and APRIL, which could promote various aspects of B-cell function (Figure 2; Table 1). Thus, these cytokines enhanced proliferation and induced isotype switching, PC formation, and Ig secretion by activated B cells (22–47) (Table 1; Figure 2). Importantly, this era also saw the identification of CD40L – transiently expressed on the surface of activated CD4+ T cells – which, together with these cytokines, was revealed to be a critical regulator of many facets of B-cell biology (48). Specifically, while CD40L (or anti-CD40 mAb) itself had minimal effect on Ab-secretion by murine and human B cells, Ab-secretion could be induced in an isotype specific manner in the presence of exogenous cytokines (Figure 2; Table 1). Thus, IL-4 and IL-13 directs naïve human B cells to switch to IgG4 and IgE expression and production, while IL-4 exerts a similar effect for inducing IgG1 and IgE by murine B cells (Table 1), with IL-5 acting synergistically with IL-4 in these murine B-cell responses (25, 28, 29, 41, 49–51). The significance of these in vitro findings was underscored by the generation of IL-4 deficient mice, which had significantly reduced production of IgE following nematode infection (52). Interestingly, IL-4-induced IgE production by human B cells could be enhanced by IL-6 or TNFα (33, 45), or inhibited by IL-8 (53), IL-12 (54), or IFN-α or IFN-γ (33, 40). While murine B cells were initially reported to be unresponsive to IL-13 (55), subsequent studies noted that IL-13 could enhance Ab production by murine B cells in vivo and that it acts directly on B cells in vitro to increase survival, thereby increasing Ab production (56). Additional support for a role for IL-13 in modulating murine B cells came from the analysis of IL-13 transgenic mice, which exhibited substantially increased levels of serum IgE, even in the absence of IL-4 (57). Similarly, while deficiency of either IL-4 or IL-13 reduced the levels of Ag-specific IgE, combined deficiency of both IL-4 and IL-13 resulted in undetectable levels of IgE (58). Thus, it is likely that IL-4 and IL-13 co-operate in both mice and humans to regulate Ig class switching, especially to IgE. IL-10 also strongly modulated the behavior of human B cells, significantly increasing the levels of IgM, IgG1, and IgA secreted by human B cells stimulated through CD40 or the BCR (42). IL-10 was also found to induce class switching in human naïve B cells to IgG1 and IgG3 (59), and together with TGF-β promoted switching to IgA (31). IL-10 also mediated the differentiation of GC and memory B cells to PCs (Table 1) (26). The ability of IL-4, IL-10, and IL-13 to induce isotype switching reflected their abilities to upregulate expression of activation induced cytidine deaminase (AICDA), an enzyme critical for class switch recombination, while IL-10 mediated PC generation by inducing BLIMP-1 (7, 8, 60). The effects of IL-10, however, appear to be species specific because serum Ig levels were unaffected in mice that were either deficient for IL-10 or that expressed IL-10 from a transgene (61, 62). Similar to CD40L, the membrane bound form of TNF-α was also found to be transiently expressed on human activated CD4+ T cells, and could co-stimulate polyclonal Ig secretion induced in human B cells co-cultured with mitogen-stimulated CD4+ T cells, or their membranes, together with IL-4 (27, 63) (Table 1).


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

Moens L, Tangye SG - Front Immunol (2014)

Cytokine-induced differentiation of human B cells in vitro: requirement for IL-21 signaling in vivo. In vitro studies demonstrated that human B cells could undergo events such as Ig class switching and differentiation to become Ig-secreting cells following stimulation with a diverse range of cytokines. However, analysis of individuals with hypomorphic mutations in genes encoding STAT3, γc (IL2RG), JAK3, or IL-21R have revealed that this pathway – activated by IL-21 – is critical for the generation of memory B cells and the establishment of Ag-specific Abs in vivo. Thus, although cytokines such as IL-4, IL-13, IL-10, and BAFF/APRIL are strong B-cell growth and differentiation factors, their function is insufficient to compensate for impaired IL-21/IL-21R signaling in vivo in the setting of generating robust, long-lived Ag-specific Ab, and memory responses. Consequently, IL-21-mediated B-cell activation is a necessary and sufficient step in the generation of protective long-lived humoral immune responses in humans.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Cytokine-induced differentiation of human B cells in vitro: requirement for IL-21 signaling in vivo. In vitro studies demonstrated that human B cells could undergo events such as Ig class switching and differentiation to become Ig-secreting cells following stimulation with a diverse range of cytokines. However, analysis of individuals with hypomorphic mutations in genes encoding STAT3, γc (IL2RG), JAK3, or IL-21R have revealed that this pathway – activated by IL-21 – is critical for the generation of memory B cells and the establishment of Ag-specific Abs in vivo. Thus, although cytokines such as IL-4, IL-13, IL-10, and BAFF/APRIL are strong B-cell growth and differentiation factors, their function is insufficient to compensate for impaired IL-21/IL-21R signaling in vivo in the setting of generating robust, long-lived Ag-specific Ab, and memory responses. Consequently, IL-21-mediated B-cell activation is a necessary and sufficient step in the generation of protective long-lived humoral immune responses in humans.
Mentions: The molecular revolution of the 1980s saw the cloning and characterization of several cytokines – IL-2, IL-4, IL-5, IL-6, IFNs – which had B-cell growth and differentiation capacity (Table 1). This continued into the 1990s with the discovery of IL-10, IL-12, IL-13, IL-15, TNFα, BAFF, and APRIL, which could promote various aspects of B-cell function (Figure 2; Table 1). Thus, these cytokines enhanced proliferation and induced isotype switching, PC formation, and Ig secretion by activated B cells (22–47) (Table 1; Figure 2). Importantly, this era also saw the identification of CD40L – transiently expressed on the surface of activated CD4+ T cells – which, together with these cytokines, was revealed to be a critical regulator of many facets of B-cell biology (48). Specifically, while CD40L (or anti-CD40 mAb) itself had minimal effect on Ab-secretion by murine and human B cells, Ab-secretion could be induced in an isotype specific manner in the presence of exogenous cytokines (Figure 2; Table 1). Thus, IL-4 and IL-13 directs naïve human B cells to switch to IgG4 and IgE expression and production, while IL-4 exerts a similar effect for inducing IgG1 and IgE by murine B cells (Table 1), with IL-5 acting synergistically with IL-4 in these murine B-cell responses (25, 28, 29, 41, 49–51). The significance of these in vitro findings was underscored by the generation of IL-4 deficient mice, which had significantly reduced production of IgE following nematode infection (52). Interestingly, IL-4-induced IgE production by human B cells could be enhanced by IL-6 or TNFα (33, 45), or inhibited by IL-8 (53), IL-12 (54), or IFN-α or IFN-γ (33, 40). While murine B cells were initially reported to be unresponsive to IL-13 (55), subsequent studies noted that IL-13 could enhance Ab production by murine B cells in vivo and that it acts directly on B cells in vitro to increase survival, thereby increasing Ab production (56). Additional support for a role for IL-13 in modulating murine B cells came from the analysis of IL-13 transgenic mice, which exhibited substantially increased levels of serum IgE, even in the absence of IL-4 (57). Similarly, while deficiency of either IL-4 or IL-13 reduced the levels of Ag-specific IgE, combined deficiency of both IL-4 and IL-13 resulted in undetectable levels of IgE (58). Thus, it is likely that IL-4 and IL-13 co-operate in both mice and humans to regulate Ig class switching, especially to IgE. IL-10 also strongly modulated the behavior of human B cells, significantly increasing the levels of IgM, IgG1, and IgA secreted by human B cells stimulated through CD40 or the BCR (42). IL-10 was also found to induce class switching in human naïve B cells to IgG1 and IgG3 (59), and together with TGF-β promoted switching to IgA (31). IL-10 also mediated the differentiation of GC and memory B cells to PCs (Table 1) (26). The ability of IL-4, IL-10, and IL-13 to induce isotype switching reflected their abilities to upregulate expression of activation induced cytidine deaminase (AICDA), an enzyme critical for class switch recombination, while IL-10 mediated PC generation by inducing BLIMP-1 (7, 8, 60). The effects of IL-10, however, appear to be species specific because serum Ig levels were unaffected in mice that were either deficient for IL-10 or that expressed IL-10 from a transgene (61, 62). Similar to CD40L, the membrane bound form of TNF-α was also found to be transiently expressed on human activated CD4+ T cells, and could co-stimulate polyclonal Ig secretion induced in human B cells co-cultured with mitogen-stimulated CD4+ T cells, or their membranes, together with IL-4 (27, 63) (Table 1).

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