The humoral arm of the immune system is critical for providing protective antibodies (Abs) against infection pathogens. The Ab pool is maintained by long-lived plasma cells (PCs), which continuously secrete Abs following their formation in response to exposure to specific antigen (Ag). In 1948, Fagraeus was the first to report that PCs are the outcome of terminal B-cell differentiation and demonstrated their importance to Ab production in vitro (1). We now know that B cells are capable of secreting multiple Ig isotypes (IgM, IgG, IgA, IgE) and subclasses of these isotypes (IgG_1–4, IgA_1–2) following the receipt of appropriate stimulate. However, today – 65 years later – our understanding of the complexities of PC development remains incomplete.

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).

The differentiation of activated B cells into PC is regulated by transcriptional programs and networks that are influenced by numerous inputs and microenvironmental factors. These include the nature of the Ag and of the responding B-cell subset, the location in which Ag encounter occurs, and the accessory cells involved (7, 8). The key transcription factors involved in regulating PC formation include the transcriptional repressors Bcl-6 and B-lymphocyte induced maturation protein (BLIMP)-1, encoded by the PRDM1 gene, as well as transcription factors PAX5, X-box-binding protein-1 (XBP-1), and IFN-induced regulatory factor 4 (IRF4) (Figure 1) (7, 8). Thus, while Bcl-6 is expressed in GC B cells and is required for the GC formation (9–11), it blocks PC differentiation and maintains a GC B-cell fate by suppressing expression of BLIMP-1, which is considered the master regulator of PC differentiation, being required for – or at least correlated with – PC commitment in mice and humans (Figure 1) (12–15). BLIMP-1 expression controls PC differentiation by restraining the mature B-cell gene expression program by down-regulating a set of genes including MHC, CIITA, PAX5, and CMYC, which result in a decrease of MHC class II expression, loss of B-cell identity, and cessation of proliferation, respectively (8, 14). BLIMP-1 may also co-ordinate expression of XBP 1, which allows expansion of the secretory apparatus necessary for high-level protein synthesis in PC differentiation (Figure 1) (16).

Cytokines represent a diverse group of small soluble proteins that can function as growth and differentiation factors in autocrine or paracrine ways. Cytokines exhibit considerable redundancy, in that many cytokines share similar functions. Through binding to specific cell surface receptors, they initiate signal transduction pathways that are critical for a diverse spectrum of functions, including induction of immune responses, cell proliferation, differentiation, and apoptosis. The key contribution of cytokines to B-cell differentiation lies in their ability to modulate expression of these transcription factors such that they regulate Ig secretion by B cells activated with mimics of T cell dependent (TD) (e.g., CD40L) or T cell independent (TI) [e.g., engaging the B-cell receptor (BCR), Toll-like receptors (TLRs)] stimuli in vitro and, by extension, in vivo. The effects of cytokines on B-cell differentiation is evidenced not only by the magnitude of the Ab response but also the quality, in terms of the particular Ig isotype(s) induced. Although many cytokines are capable of promoting B-cell differentiation, the relative roles of specific factors, and the hierarchy of the interactions between several cytokines, has only emerged in the last 10 years.

The concept that cross-linking of the BCR initiates B-cell activation and facilitates these cells to respond to T-cell-derived soluble factors and undergo proliferation and differentiation to become Ab-secreting cells was first appreciated in the 1970s (17–20). The different factors were classically grouped as T cell-replacing factors, some of which influence the replication of B cells (B-cell growth factor), while others directly cause B-cell differentiation to Ab-secretion cells (B-cell differentiation factor) (21). While it gradually emerged that these T cell-derived factors are Ag non-specific, genetically non-restricted, and are indeed involved in the differentiation of B cells into Ab-secreting cells, at this time no single factor had been isolated or molecularly cloned, and it remained unknown how many factors were actually involved in, or required for, B-cell terminal differentiation (22, 23).

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).

IL-2 has had a long history of being documented of enhancing Ig secretion by activated human B cells (Table 1) (38, 39). Consistent with the structural and functional similarities between IL-2 and IL-15, it was not surprising that IL-15 could also stimulate proliferation and induce secretion of IgM, IgG₁, and IgA, but not IgG₄ or IgE, by CD40L-primed B cells. This activity of IL-15 was comparable to that of IL-2 (24).

More recently, the TNF-related molecule BAFF, and its homolog APRIL, has emerged as a global regulator of B-cell development and function (64–66). While a primary role for BAFF lies in the ability to promote the survival of B cells at the transitional stage of development (65), both BAFF and APRIL can also induce the molecular events associated with isotype switching to IgG and IgA, and to IgE in the presence of IL-4. Furthermore, the secretion of these Ig isotypes occurred when the B cells also received signals through the BCR (64, 66). BAFF and APRIL can also sustain the survival of PCs in vivo and in vitro (66, 67). BAFF functions by binding to the surface receptors BAFF-R, TACI, or BCMA; APRIL can also activate B cells by binding to TACI and BCMA (65, 66) (Table 1). Interestingly, these effects of BAFF and APRIL appear to be mediated through different receptors. Thus, the pro-survival effects of BAFF on transitional and naïve B cells are delivered through BAFF-R, while this effect on PCs occurs predominantly through BCMA. On the other hand, BAFF-R and TACI mediates isotype switching to IgG, IgA, and IgE induced by BAFF and APRIL, respectively (64–66). Lastly, heparan sulfate proteoglycans can also act as a receptor for APRIL, and this appears to be important for mediating the pro-survival effects of APRIL on BM PCs (67–69).

Collectively, it is clear that myriad cytokines and combinations thereof, are capable of eliciting activation and terminal differentiation of human B cells to differing extents. However, with the discover of IL-21 in 2001, and the subsequent characterization of its function on human and murine B cells during the following decade, the physiological significance of many of these factors in initiating humoral immune responses needs to be re-addressed as IL-21 has emerged as the most potent inducer of B cell differentiation.

IL-21 belongs to the type I family of cytokines that also includes IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to and form a complex with the common γ-chain (γc) and their private receptors (70–73). The IL-21 receptor (IL-21R) is expressed by fibroblasts, keratinocytes, and intestinal epithelial cells, but more importantly is also expressed on lymphocytes (T, B, NK cells), macrophages, and dendritic cells, and the levels of expression can be increased following cellular activation (70, 71, 74–77). IL-21 is predominantly produced by activated CD4⁺ T cells and NKT cells (78–80), with the greatest production being by Tfh and GC Tfh cells (4–6). Akin to most cytokines, IL-21 exerts its effect by activating Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways, specifically Jak1 and Jak3, and STAT1, STAT3, and to a lesser extent STAT5 (72, 81–84). The initial description of IL-21 hinted at its B-cell tropism, inasmuch that Parrish-Novak et al. showed that IL-21 significantly co-stimulated proliferation of human blood B cells induced by anti-CD40 mAbs (71). Since then, several studies have confirmed that IL-21 is an important regulator of B-cell activation, proliferation, PC differentiation, and Ab-secretion in both mice and humans.

The ability of IL-21 to guide multiple fates in activated B cells – class switching to express downstream Ig isotypes, commitment to the PC lineage, as well as formation of GCs and memory B cells – reflects the ability of IL-21 to induce the molecular machinery required for these processes. Thus, IL-21 is capable of inducing expression of AICDA, BLIMP1/PRDM1, and XBP-1, as well as reducing expression of PAX5, in both human and murine B cells (Figure 3) (60, 83, 84, 86, 98). Collectively, these factors regulate class switching and PC formation (8). Interestingly, the ability of IL-4 to suppress the stimulatory effects of IL-21 on naïve B cells correlated with a reduction in BLIMP-1 expression (60). IL-21 could also induce BCL-6 (83, 86, 89, 92, 98), which would contribute to GC formation in vivo (Figure 3) (8). Thus, in the setting of TD B-cell activation, Tfh-derived IL-21 can induce B cells to express all of the machinery required to undergo the major fates of differentiation: GC B cells by induction of Bcl-6; PCs following induction of BLIMP-1, and class switched B cells by inducing AICDA. It is likely that IL-21 induces expression of these opposing transcriptional regulators (i.e., BLIMP-1, Bcl-6) in distinct subsets of B cells that will ultimately develop into either PC or memory B cells. However, these outputs will ultimately reflect the balance of signals received and integrated by the B cells, with the effect of IL-21 being influenced by inputs delivered via receptors including the BCR, other complimentary cytokine, and co-stimulatory receptors.

As IL-21 can activate several STATs (73), the relative contribution of individual STAT molecules has been assessed. Diehl et al. demonstrated that constitutive activation of STAT3 in primary human B cells induced BLIMP-1 expression and initiated B cell differentiation, yielding cells with a phenotype (CD38^highCD20⁻CD19^lowHLA-DR^lowCD138⁺) consistent with PC as well as enhanced Ab-secretion (84). Importantly, up-regulation of BLIMP-1 alone was not sufficient for differentiation of primary human B cells into PCs; this event also required concomitant down-regulation of BCL-6 (84). This study was the first to propose that STAT3 was the predominant mediator of the differentiation effects that IL-21 has on human B cells. These were largely confirmed by the demonstration that induction of PRDM1, XBP-1, and BCL-6 by IL-21 were abolished in naïve B cells isolated from individuals with hypomorphic mutations in STAT3, while these responses were unaffected by loss-of-function mutations in STAT1 (83, 107). Intriguingly, IL-21-induced expression of AICDA in naïve B cells, as well as of PRDM1 and XBP1 in memory B cells, still occurred despite the presence of hypomorphic STAT3 mutations, suggesting that class switching in naïve B cells and PC differentiation from memory B cells requires less STAT3 function than does the generation of PC from naïve B cells (83, 107).

Interestingly, high-affinity signaling through the BCR on immortalized B-cell lines can activate STAT3 (108). Similarly, CD40L enhanced the expression of BLIMP-1 induced by IL-21/STAT3 signaling in a GC B cell-like human cell line, thereby maximizing PC differentiation (109). Thus, it is possible that signals integrated in B cells through receptors such as CD40 and the BCR can amplify the effects of IL-21 by modulating activating or function of STAT3. It is also worth noting that STAT3 activation is important for the survival of multiple myeloma cells (110). As IL-21 is also anti-apoptotic for myeloma cells, it is tempting to speculate that IL-21 could contribute to STAT3 activation in vivo in the setting of this malignancy. Collectively, these studies have illuminated the pivotal role of IL-21-mediated STAT3 signaling in guiding key events of human B-cell differentiation.

Primary immunodeficiencies (PIDs) result from monogenic mutations that compromise the ability of affected individuals to elicit appropriate immune responses. Consequently, these individuals exhibit susceptibility to infectious diseases and are often unable to respond to vaccination. As the genetic lesion is known in many PIDs, these conditions can reveal the unique functions of specific genes and related signaling pathways in immune cells and the importance of these pathways in productive and protective immune responses. Thus, analysis of PIDs can shed new light on the requirements for lymphocyte development and function. Indeed, several PIDs have confirmed the critical role played by IL-21 in humoral immunity in humans.

Heterozygous mutations in STAT3 are the major cause of autosomal dominant hyper-IgE syndrome (AD-HIES) (111, 112), a multisystem disease affecting the immune and musculoskeletal systems (113, 114). Immunological defects include skin lesions, recurrent mucocutaneous invasive infections with S. aureus and Candida. These patients have normal serum levels of IgM, IgG, and IgA but increased levels of IgE (113, 114). Although the frequencies of total peripheral blood B cells are not significantly different between AD-HIES patients and control individuals, STAT3 deficiency impaired the in vivo generation of human memory B cells as well as the generation of Ag-specific Ab-secreting B cells and high-affinity serum Abs (Figure 2) (83, 107). This reduced number of memory B cells is in line with previously reported defective functional Ab responses in AD-HIES patients (115–118). Cytokines known to be involved in human B cell differentiation are IL-6, IL-10, and IL-21. Consistent with reduced memory B cells and poor induction of Ag-specific Ab responses in AD-HIES, naïve B cells from these patients were unable to respond to the stimulatory effects of IL-10 or IL-21 with respect to differentiation into PC in vitro (Figure 3). STAT3 mutations also compromised the ability of IL-21 to prime B cells to the stimulatory effects of IL-2, inasmuch that induction of CD25 – and subsequent responsiveness to IL-2 – was attenuated on IL-21-stimulated STAT3-deficient human naïve B cells (104). These findings revealed that STAT3 plays a non-redundant role in generating Ag-specific memory B cells and Ab-secreting cells in vivo. However, it remained to be determined which STAT3-activating cytokine was requisite for these effects. This became clearer by examining patients with mutations in IL2RG, encoding γc, or JAK3, which associates with γc and delivers signals downstream of γc-containing cytokine receptors (73), that cause X-linked severe combined immunodeficiency (X-SCID) or one type of autosomal recessive (AR) SCID, respectively (73, 119). These PIDs are fatal unless treated by hematopoietic stem cell transplant (HSCT) (119).

X-linked severe combined immunodeficiency and JAK3 deficiency are characterized by a lack of T and NK cells but normal or increased numbers of B cells. However, due to the lack of CD4⁺ T cell help, B cell responses are impaired (119). While HSCT corrects the humoral defect in ~50% of patients, the remainder still requires ongoing Ig replacement therapy (120). One of the explanations for this is split chimerism, where donor-derived T cells successfully engraft in the recipient, but autologous host-derived B cells persist (120). Thus, despite the presence of functional CD4⁺ T cells, the IL2G/JAK3 mutant B cells remain unable to respond to T-cell-derived helper signals, rendering the patient immunodeficient with respect to humoral immune responses (119, 120). We took advantage of this chimeric state to examine the B-cell compartment of X-SCID and JAK3 deficient patients who had undergone HSCT (121). Although IL-2RG/JAK3 mutant naïve B cells responded normally to co-stimulatory signals delivered through the BCR, TLRs, and receptors for IL-10, IL-13, and even IL-4 [which can also signal through the IL13R; (73)], these B cells were completely unresponsive to IL-21. Naïve B cells from these individuals also failed to differentiate into memory cells in vivo (Figures 2 and 3). Thus, despite intact responsiveness to a suite of well-characterized B-cell growth and differentiation factors, the ability to receive signals through a γc-binding/JAK3-activating cytokine is a critical and rate-limiting step for the establishment of humoral immunity in humans (Figure 2) (121). Given the potency that IL-21 exerts on human B-cell differentiation, it was highly likely that this was the key γc-binding/JAK3-activating cytokine involved in human B-cell responses in vivo.

This was confirmed by the recent identification of individuals with homozygous loss-of-function mutations in IL21R that causes a novel PID, features of which include occasionally reduced serum IgG levels, poor Ab responses following vaccination with TD Ags (122), and a paucity of circulating memory B cells, including those expressing class switched Ig isotypes (107, 122). Not surprisingly, IL-21R-deficient naïve B cells exhibited impaired IL-21-induced proliferation, Ig class switching, and PC differentiation in vitro. This is consistent with a failure of IL-21 to mediate the acquisition of expression of AICDA, PRDM1, and XBP1 in these cells, and mirrors the humoral immune defects observed in these patients. The cellular and molecular characterization of these patients has definitively established the criticality of IL-21 in establishing long-lived humoral immune responses. Furthermore, the finding that B cells with mutations in IL2RG, JAK3, or STAT3 phenocopy IL-21R-deficient B cells, with respect to memory cell formation and responsiveness to IL-21, demonstrates that signaling downstream of the IL-21R/γc complex via JAK3 and STAT3 is essential for the effector function of IL-21 on B-cell differentiation in terms of generating efficient Ag-specific humoral immune responses (Figures 2 and 3). However, since serum levels of total IgM, IgG, and IgA are largely normal in most patients with mutations in either STAT3 or IL-21R, it is clear that the production of basal Ig is not dependent on IL-21R/STAT3 signaling. Indeed, as we have previously proposed (83), this is likely achieved by the interplay between ligands that do not signal via STAT3 – these could include many of the cytokines and factors detailed in this review (see Table 1), such as IL-4, IL-13, BAFF/APRIL as well as TLR ligands. Despite the availability of these ligands in STAT3- and IL-21R-deficient patients, and their ability to signal normally in IL-21R/STAT3-deficient B cells, these factors are collectively unable to compensate for impaired IL-21R signaling in order to generate a robust, long lasting Ag-specific Ab response.

Intriguingly, IL-21R-deficient individuals also have elevated levels of serum IgE (122), which is obviously also a feature of AD-HIES (113, 114, 116). Thus, it is likely that IL-21 also plays an important role in regulating IgE production by human B cells. However, whether this is due to a direct effect of IL-21 on B cells, or operates through an intermediate cell type [e.g., by inducing production of IFNγ by T cells and NK cells; (40, 100)] remains to be determined.

Lastly, it is worth commenting that prior to the discovery and subsequent characterization of IL-21, IL-10 was considered to be the most efficient cytokine capable of activating human B cells (31, 42, 48, 59). As IL-10 can also activate STAT3 (73), and STAT3-deficient human naïve B cells are unable to respond to the PC-inducing effects of IL-10 (83), it is possible that the humoral defects in AD-HIES patients reflects an inability to respond to not only IL-21 but also IL-10. However, since individuals with mutations in IL-10 or IL-10R have intact specific Ab responses to vaccines (123), it is possible the IL-10 plays only a minor role in regulating human B-cell function in vivo. There are caveats to this conclusion, however, as most patients examined were young (<10 years old), and they also suffered from early onset inflammatory bowel disease (123). Thus, it remains plausible that IL-10 does contribute to B-cell function in healthy adults.

Just as impaired signaling via IL-21 manifests as humoral immunodeficiency, aberrant or excessive IL-21-induced B-cell activation has been associated with the development of Ab-mediated autoimmune states in both murine models and human.

The first indication of a potential involvement of IL-21 in autoimmunity was the finding that IL-21 was overexpressed in several strains of mice (e.g., BXSB-Yaa, B6.Sle1-Yaa, Sanroque, MRL/MpJ-FAS^lpr/lpr/J) that develop lupus-like disease (86, 124, 125). Furthermore, in vivo blockade of IL-21 ameliorated disease progression and severity in some of these settings (126–128), as well as in animal models of rheumatoid arthritis (129) and Sjogren’s syndrome (130). This was followed by the demonstration of elevated expression and/or production of IL-21 in human autoimmune conditions including SLE (131–134), rheumatoid arthritis (135), and Sjogren’s syndrome (136). Consistent with these findings, as well as with the recognition that IL-21 is predominantly produced by Tfh cells, it was perhaps not surprising that circulating Tfh-like cells have been detected in a broad array of autoimmune conditions including not only SLE, rheumatoid arthritis, and Sjogren’s syndrome, but also multiple sclerosis, autoimmune thyroid disease, myasthenia gravis, and juvenile dermatomyositis [reviewed in Ref. (6, 137)]. Importantly, the increases in Tfh cells generally correlated with numerous indices of disease severity, such as titers of autoAb, numbers of Ab-secreting plasmablasts, clinical scores, and even levels of serum IL-21. Furthermore, the expanded population of Tfh cells, as well as clinical features of each of these diseases, could be reduced following initiation and continuation of immunosuppressive treatments [reviewed in Ref. (6, 137)]. Independent confirmation that IL-21/IL-21R may be involved in the development of autoimmune diseases came from genome-wide association studies. Specifically, polymorphisms in either IL-21 or IL-21R genes have been identified that associated with SLE, RA, and primary Sjogren’s syndrome (138–141). Collectively, there is convincing evidence that IL-21 – most likely produced by Tfh cells – plays a pathological role in the initiation, development, and/or progression of several human autoimmune diseases caused by the production of autoantibodies.

B cells play myriad fundamental roles in providing protective immunity against infection. However, the most prominent of these is the production of Ag-specific Ab following the terminal differentiation of B cells into long-lived PCs. This event is key to the establishment of long-term humoral immunity and memory, and underlies the success of most currently available vaccines. The criticality of Ab production by B cells to human health is evidenced by the pathological consequences of hypogammaglobulinemia, resulting in immunodeficiency. Conversely, the dysregulated production of excessive quantities of self-reactive Abs can be deleterious in the setting of autoimmunity. The detailed characterization of the effects of cytokines on B cells – from studies in genetically manipulated mice, in vitro cultures of human and murine B cells, and analysis of humans with specific PIDs – have revealed the central role that IL-21 has in generating memory B cells and specific Abs following exposure to TD Ags. Remarkably, alternative signals that could be integrated in B cells through other cytokine or co-stimulatory receptors are insufficient to initiate such B-cell responses when the IL-21/IL-21R signaling pathway is compromised. This paves the way for developing directed therapies to improve immune responses to vaccines or in immunocompromised individuals. Supporting this concept is the finding that administration of IL-21 to macaques increased frequencies of memory B cells as well as titers of virus-specific IgG (142). Conversely, therapies aimed at blocking the action of IL-21, either by directly targeting IL-21 itself or indirectly targeting Tfh cells or appropriate signaling molecules downstream of the IL-21R, so as to restrain the differentiation of rogue, autoreactive B cells into PCs, represents a feasible strategy for the treatment of various autoimmune diseases, as evidenced from numerous murine models (126–129, 143). Hopefully these findings will see successful translation to the clinic, thereby offering new hope for the treatment of these immune dyscrasias.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.