IL-21 Receptor Is Required for the Systemic Accumulation of Activated B and T Lymphocytes in MRL/MpJ-Fas<i>lpr/lpr</i>/J Mice

Rankin, Andrew L.; Guay, Heath; Herber, Deborah; Bertino, Sarah A.; Duzanski, Tatyana A.; Carrier, Yijun; Keegan, Sean; Senices, Mayra; Stedman, Nancy; Ryan, Mark; Bloom, Laird; Medley, Quintus G.; Collins, Mary; Nickerson‐Nutter, Cheryl; Craft, Joe; Young, Deborah; Dunussi-Joannopoulos, Kyri

doi:10.4049/jimmunol.1003871

Cited by 75 publications

(83 citation statements)

References 81 publications

(107 reference statements)

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“…Elevated IL-21 levels were found in lupus-prone BXSB.Yaa mice, and autoimmune features were attenuated in BXSB.Yaa and MRL-Fas lpr mice following genetic deletion of IL-21R or IL-21 blockade (20)(21)(22)(23). In patients with lupus, an association between polymorphisms in the IL-21 and IL-21R gene and disease susceptibility was reported, along with increased circulating and intracellular levels of IL-21 (24)(25)(26)(27)(28).…”

Section: Nterleukin-21 Is a Member Of The Type I Cytokine Family Wimentioning

confidence: 96%

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

Nguyen

Rus

Chen

et al. 2016

The Journal of Immunology

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IL-21 promotes B cell and CTL responses in vivo, conferring IL-21 with a role in both humoral and cellular responses. Because CTL can target and eliminate autoreactive B cells, we investigated whether IL-21R signaling in CD8 T cells would alter the expansion of autoreactive B cells in an autoimmune setting. We addressed this question using the parent→F1 murine model of acute and chronic (lupus-like) graft-versus-host disease (GVHD) as models of a CTL-mediated or T-dependent B cell–mediated response, respectively. Induction of acute GVHD using IL-21R–deficient donor T cells resulted in decreased peak donor CD8 T cell numbers and decreased CTL effector function due to impaired granzyme B/perforin and Fas/Fas ligand pathways and a phenotype of low-intensity chronic GVHD with persistent host B cells, autoantibody production, and mild lupus-like renal disease. CTL effector maturation was critically dependent on IL-21R signaling in Ag-specific donor CD8, but not CD4, T cells. Conversely, treatment of DBA/2J→F1 chronic GVHD mice with IL-21 strongly promoted donor CD8 T cell expansion and rescued defective donor anti-host CTLs, resulting in host B cell elimination, decreased autoantibody levels, and attenuated renal disease, despite evidence of concurrently enhanced CD4 help for B cells and heightened B cell activation. These results demonstrate that, in the setting of lupus-like CD4 T cell–driven B cell hyperactivity, IL-21 signaling on Ag-specific donor CD8 T cells is critical for CTL effector maturation, whereas a lack of IL-21R downregulates CTL responses that would otherwise limit B cell hyperactivity and autoantibody production.

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Section: Nterleukin-21 Is a Member Of The Type I Cytokine Family Wimentioning

confidence: 96%

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

Nguyen

Rus

Chen

et al. 2016

The Journal of Immunology

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“…42 Consistently, when MLR lpr mice were made deficient in IL-21R, they showed reduced splenomegaly, lymphadenopathy and autoantibody production, and lacked spontaneous GC formation and plasmacell accumulation. 43 Moreover, the role of IL-21 is also shown in another model of murine lupus, NZB/W F1 mice, which exhibit clinical features that resemble those of human SLE, including autoantibody production and immune complex-mediated nephritis. 44,45 Upon intranasal administration of anti-CD3 antibodies, NZB/W F1 mice exhibited suppressed lupus development characterized by reduced levels of autoantibodies and diminished glomerulonephritis.…”

Section: T Fh Cells In Murine Models Of Autoimmune Diseasesmentioning

confidence: 99%

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

Shekhar

Yang

2012

Cell Mol Immunol

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Follicular helper T (T FH ) cells represent a distinct subset of CD4 1 helper T (T H ) cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile (Bcl6), surface marker expression (CXCR5, PD-1, ICOS and CD40L) and cytokine production pattern (IL-21 and IL-6). T FH cells provide help to B cells both to form germinal centers (GCs) and to differentiate into memory B cells and plasma cells for generation of humoral responses. However, there is emerging evidence that implicates T FH cells in the development of various human pathologies, such as autoimmune diseases, immunodeficiency and lymphoma. This review focuses on the current progress in this area including mouse and human studies. A clearer understanding of the mechanisms of T FH cell-mediated immunity and pathology may be exploited for rational development of therapeutic strategies.

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“…Treatment with IL-21R.Fc fusion protein in vivo has demonstrated partial antiinflammatory activity in mouse models in which IL-21R deficiency completely abolished disease (4,(8)(9)(10)(11). This may be due to a greater role of IL-21 in the early initiation, rather than the maintenance, of disease.…”

mentioning

confidence: 99%

“…In mouse models of spontaneous autoimmunity, such as systemic lupus erythematosus (SLE), type 1 diabetes mellitus, and arthritis, IL-21/IL-21 receptor (IL-21R) deficiency completely abrogates all manifestations of disease (1,4). Furthermore, in a model of chronic viral infection characterized by attenuated CD81 T cell activity, IL-21 controls viremia by maintaining the antiviral activity of so-called "exhausted" CD81 T cells (5).…”

mentioning

confidence: 99%

Interleukin‐21 Receptor Blockade Inhibits Secondary Humoral Responses and Halts the Progression of Preestablished Disease in the (NZB × NZW)F1 Systemic Lupus Erythematosus Model

Zhang

Chan

et al. 2015

Arthritis & Rheumatology

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Objective. Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is driven in part by chronic B and T lymphocyte hyperresponsiveness to self antigens. A deficiency of interleukin-21 (IL-21) or IL-21 receptor (IL-21R) in mice dramatically reduces inflammation and B and T cell activation in models of autoimmunity, including SLE. However, whether IL-21 is essential for the maintenance and amplification of preestablished inflammation has not been widely examined in various animal models. The purpose of this study was to examine the impact of novel mouse IL-21R neutralizing antibodies on recall responses to antigen challenge and on disease progression in the (NZB 3 NZW)F1 (NZB/NZW) mouse model of SLE.Methods. Humoral and cellular immune responses to immunization with sheep red blood cells (SRBCs) were measured in mice dosed with IL-21R blocking antibodies. Progression of nephritis and markers of immune activation was monitored in NZB/NZW mice following different anti-IL-21R treatment regimens.Results. IL-21R blockade specifically inhibited secondary IgG responses to SRBC immunization. In NZB/NZW mice, IL-21R blockade completely inhibited the onset of nephritis, which was associated with dramatic reductions in splenomegaly and in B cell and T cell activation. When administered to mice with preexisting disease, anti-IL-21R antibody halted the disease progression and mortality and reversed the nephritis in a subset of mice. Furthermore, treatment cessation was not followed by rapid reemergence of disease. Conclusion. Our results highlight the importance of IL-21 in promoting humoral recall responses and in sustaining autoimmune inflammation.Interleukin-21 (IL-21), a member of the type I/ common g-chain family of cytokines, is in many respects, the quintessential "helper" cytokine, in that it is expressed primarily by CD41 T cells and induces effector mechanisms in all lymphocytes (1). Although dispensable for normal B and T cell development, IL-21 is required for T celldependent affinity-matured antibody production in response to immunization, and it drives autoantibody production in rodent models of lupus, type 1 diabetes mellitus, and arthritis (1). A key driver of germinal center formation, IL-21 acts on both B cells and, in an autocrine manner, follicular helper T (Tfh) cells to sustain B cell maturation, antibody class switching, and ultimately, plasma cell formation (2). Similarly, in in vitro assays for human T cell-dependent B cell activation, IgG and IgA production is entirely IL-21 dependent (3). IL-21 also stimulates CD41 and CD81 T cell differentiation and production of multiple proinflammatory mediators, such as IL-17, interferon-g (IFNg), chemokines, granzymes, and perforin (1).In mouse models of spontaneous autoimmunity, such as systemic lupus erythematosus (SLE), type 1 diabetes mellitus, and arthritis, IL-21/IL-21 receptor (IL-21R) deficiency completely abrogates all manifestations of disease (1,4). Furthermore, in a model of chronic viral infection characterized by attenuated CD81 T c...

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IL-21 Receptor Is Required for the Systemic Accumulation of Activated B and T Lymphocytes in MRL/MpJ-Faslpr/lpr/J Mice

Cited by 75 publications

References 81 publications

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

Interleukin‐21 Receptor Blockade Inhibits Secondary Humoral Responses and Halts the Progression of Preestablished Disease in the (NZB × NZW)F1 Systemic Lupus Erythematosus Model

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