IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo

Recher, Mike; Berglund, Lucinda J.; Avery, Danielle T.; Cowan, Morton J.; Gennery, Andrew R.; Smart, Joanne; Peake, Jane; Wong, Melanie; Pai, Sung-Yun; Baxi, Sachin N.; Walter, Jolán E.; Palendira, Umaimainthan; Tangye, Gillian A.; Rice, M. S.; Al‐Herz, Waleed; Oettgen, Hans C.; Eibel, Hermann; Puck, Jennifer M.; Cattaneo, Federica; Ziegler, John B.; Giliani, Silvia; Tangye, Stuart G.; Notarangelo, Luigi D.

doi:10.1182/blood-2011-06-362533

Cited by 134 publications

(146 citation statements)

References 52 publications

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“…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).…”

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.

108

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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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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.

108

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“…B lymphocytes are present, but intrinsic signaling defects render them nonfunctional. 2,3 Since the first hematopoietic stem cell transplant (HSCT) to correct the immunodeficiency in SCID in 1968, incremental improvements in techniques and supportive care have led to better survival. 4,5 However, most publications described long-term outcome of the entire SCID cohort, irrespective of the genotypic and phenotypic diversity.…”

Section: Introductionmentioning

confidence: 99%

Long-term outcome of hematopoietic stem cell transplantation for IL2RG/JAK3 SCID: a cohort report

Hamid

Slatter

McKendrick

et al. 2017

Blood

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“…IL-21 is a member of the common g-chain cytokine family shown to play a central role in plasmablast and plasma cell differentiation during T cell-dependent B cell responses (19,20). In humans, IL-21 is mainly produced by activated peripheral CD4 + T cells and follicular Th cells (21,22).…”

mentioning

confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo

Abstract: SCID resulting from mutations in

Cited by 134 publications

References 52 publications

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

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

Long-term outcome of hematopoietic stem cell transplantation for IL2RG/JAK3 SCID: a cohort report

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

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IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo

Abstract: SCID resulting from mutations in

Cited by 134 publications

References 52 publications

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

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

Long-term outcome of hematopoietic stem cell transplantation for IL2RG/JAK3 SCID: a cohort report

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

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

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