Cutting Edge: IL-21 Is a Switch Factor for the Production of IgG1 and IgG3 by Human B Cells

Pène, Jérôme; Gauchat, Jean‐François; Lécart, Sandrine; Drouet, Élodie; Guglielmi, Paul; Boulay, Véra; Delwail, Adriana; Foster, Donald M.; Lecron, Jean‐Claude; Yssel, Hans

doi:10.4049/jimmunol.172.9.5154

Cited by 279 publications

(238 citation statements)

References 22 publications

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“…2 and data not shown). The IL-21 pathway has been shown to play a key role in isotype switching to IgG (14,29). In addition, naive IL-21R.KO mice have reduced total serum IgG and elevated serum IgE Ab titers (14).…”

Section: Secondary Ab Responses Are Diminished In Il-21rko Micementioning

confidence: 99%

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Rankin

MacLeod

Keegan

et al. 2011

The Journal of Immunology

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Development of long-term humoral immunity, characterized by the formation of long-lived plasma cells (PCs) in the bone marrow and memory B cells, is a critical component of protective immunity to pathogens, and as such it is the major goal of vaccination. However, the mechanisms involved in the generation of long-term humoral immunity remain poorly understood. In this study, we used IL-21R–deficient (IL-21R.KO) mice to examine the role of the IL-21 pathway in the development of the B cell memory response. Primary IgG serum Ab responses to the T cell-dependent Ag 4-hydroxy-3-nitrophenylacetyl (NP) hapten conjugated to chicken γ globulin were delayed in IL-21R.KO mice, but reached normal titers within 3 to 4 wk of immunization. IL-21R.KO mice formed germinal centers and generated normal numbers of PCs in their bone marrow. Additionally, memory B cell formation was similar in wild-type and IL-21R.KO mice. However, NP-specific memory B cells and PCs failed to expand following secondary immunization of IL-21R.KO mice, and consequently, secondary IgG Ab responses to NP hapten conjugated to chicken γ globulin were significantly impaired. These results identify the IL-21 pathway as a critical component of the memory B cell response.

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Section: Secondary Ab Responses Are Diminished In Il-21rko Micementioning

confidence: 99%

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Rankin

MacLeod

Keegan

et al. 2011

The Journal of Immunology

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“…In T cells, IL-21 can act as a comitogen and cooperates with IL-7 and IL-15 to expand CD8 + T cells (3), promotes Th17 differentiation (4)(5)(6), and induces BCL6 expression (7) to promote T follicular helper cell development (8,9). In B cells, IL-21 promotes plasma cell differentiation (10,11), and in combination with IL-4, drives IgG1 and IgG3 class switch (11,12). Defective signaling by IL-21 appears to substantially explain the B-cell defect observed in patients with XSCID (11,13).…”

Section: Il-21 | T Cells | Stats | Ifn-γ | Ad-hiesmentioning

confidence: 99%

Opposing roles of STAT1 and STAT3 in IL-21 function in CD4 ⁺ T cells

Wan

Andraski

Spolski

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

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IL-21 is a type I cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4 + T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4 + T cells. RNA-Seq analysis of CD4 + T cells from Stat1-and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3. Moreover, opposing actions of STAT1 and STAT3 on IFN-γ expression in CD4 + T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4 + T cells from patients with autosomal dominant hyperIgE syndrome, which is caused by STAT3 deficiency, as well as in cells from STAT1 gain-of-function patients. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions.) is a type I cytokine that signals via a receptor composed of IL-21R and the common cytokine receptor γ-chain, γ c (1). γ c is also shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is mutated in humans with X-linked severe combined immunodeficiency (XSCID), a disease characterized by the absence of T and natural killer (NK) cells and the presence of nonfunctional B cells (2). IL-21 is primarily produced by CD4 + T cells and natural killer T (NKT) cells, but it has pleiotropic actions on both adaptive and innate immune cells, including T, B, NK, NKT, and dendritic cells (1). In T cells, IL-21 can act as a comitogen and cooperates with IL-7 and IL-15 to expand CD8 + T cells (3), promotes Th17 differentiation (4-6), and induces BCL6 expression (7) to promote T follicular helper cell development (8, 9). In B cells, IL-21 promotes plasma cell differentiation (10, 11), and in combination with IL-4, drives IgG1 and IgG3 class switch (11,12). Defective signaling by IL-21 appears to substantially explain the B-cell defect observed in patients with XSCID (11, 13). Furthermore, IL-21 can enhance the cytotoxic activity of NK and NKT cells (1) and induce the apoptosis of conventional dendritic cells (14).IL-21 activates multiple signaling pathways, including the JAK-STAT, PI 3-kinase (PI3K), and MAPK pathways (15). Of these, the JAK-STAT pathway has been most extensively studied. IL-21 induces phosphorylation of JAK1 and JAK3, which in turn leads to phosphorylation and nuclear translocation of STAT3, which then binds to IFN-γ-activated sequence (GAS) motifs and modulates expression of IL-21-responsive genes. IL-21 also activates STAT1, but the function of IL-21-activated STAT1 is largely unknown, although IL-21 was suggested to use STAT1 to promote CD8 + T-cell cytotoxicity and ap...

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“…In addition, IL-21 signalling is required for IgG1 production, effi cient GC formation, affi nity maturation and LLPC formation, but not for B mem cell development in mice 9 -12 . IL-21 induces class switch recombination (CSR) to IgG 13 and Blimp1 expression in B cells through transcriptional activation of the Blimp1-enoding Prdm1 gene via cooperation of Irf4 and Stat3 (refs 14,15), and thus PC diff erentiation 14,16 -18 . IL-21 was also reported to be required for generation of Tfh cells, which themselves produce IL-21 (refs 19,20), but this idea has recently been questioned 9 -11 .…”

mentioning

confidence: 99%

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

et al. 2011

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In response to T cell-dependent antigens, B cells proliferate extensively to form germinal centres (GC), and then differentiate into memory B (B mem ) cells or long-lived plasma cells (LLPCs) by largely unknown mechanisms. Here we show a new culture system in which mouse na ï ve B cells undergo massive expansion and isotype switching, and generate GC-phenotype B (iGB) cells. The iGB cells expressing IgG1 or IgM / D, but not IgE, differentiate into B mem cells in vivo after adoptive transfer and can elicit rapid immune responses with the help of cognate T cells. Secondary culture with IL-21 maintains the proliferation of the iGB cells, while shifting their in vivo developmental fate from B mem cells to LLPCs, an outcome that can be reversed by withdrawal of IL-21 in tertiary cultures. Thus, this system enables in vitro manipulation of B-cell fate, into either B mem cells or LLPCs, and will facilitate dissection of GC-B cell differentiation programs.

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Cutting Edge: IL-21 Is a Switch Factor for the Production of IgG1 and IgG3 by Human B Cells

Cited by 279 publications

References 22 publications

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Opposing roles of STAT1 and STAT3 in IL-21 function in CD4 ⁺ T cells

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

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Cutting Edge: IL-21 Is a Switch Factor for the Production of IgG1 and IgG3 by Human B Cells

Cited by 279 publications

References 22 publications

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Opposing roles of STAT1 and STAT3 in IL-21 function in CD4 + T cells

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

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Opposing roles of STAT1 and STAT3 in IL-21 function in CD4 ⁺ T cells