A Critical Role for IL-21 in Regulating Immunoglobulin Production

Ozaki, Katsutoshi; Spolski, Rosanne; Feng, Carl G.; Qi, Chen‐Feng; Cheng, Jun; Sher, Alan; Morse, Herbert C.; Liu, Chengyu; Schwartzberg, Pamela L.; Leonard, Warren J.

doi:10.1126/science.1077002

Cited by 886 publications

(993 citation statements)

References 29 publications

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“…On the other hand, IL-21 is critical for T FH cells to promote B-cell somatic hypermutation and immunoglobulin class switching. 22 T FH cells can also produce other cytokines, similar to other T H cells such as T H1 and T H2 cells, which may be relevant to the development of various classes of antibodies.…”

Section: Characteristics Of T Fh Cellsmentioning

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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Section: Characteristics Of T Fh Cellsmentioning

confidence: 99%

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

Shekhar

Yang

2012

Cell Mol Immunol

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“…Thus, there could be competition for homeostatic cytokines in the replete host. It is also important to mention the newly discovered cytokine IL-21, which shares homology with IL-2 and IL-15 and binds their common γc receptor [44,45]. This cytokine might augment the function of adoptively transferred tumor-specific CD8 + T cells [17,46] and is the subject of ongoing investigations.…”

Section: Evidence For the Presence Of Homeostatic Cellular Cytokine 'mentioning

confidence: 99%

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

Klebanoff

Khong

Antony

et al. 2005

Trends in Immunology

411

288

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Lymphodepletion followed by adoptive cell transfer (ACT) of autologous, tumor-reactive T cells boosts antitumor immunotherapeutic activity in mouse and in humans. In the most recent clinical trials, lymphodepletion together with ACT has an objective response rate of 50% in patients with solid metastatic tumors. The mechanisms underlying this recent advance in cancer immunotherapy are beginning to be elucidated and include: the elimination of cellular cytokine 'sinks' for homeostatic γ C -cytokines, such as interleukin-7 (IL-7), IL-15 and possibly IL-21, which activate and expand tumor-reactive T cells; the impairment of CD4 + CD25 + regulatory T (Treg) cells that suppress tumorreactive T cells; and the induction of tumor apoptosis and necrosis in conjunction with antigenpresenting cell activation. Knowledge of these factors could be exploited therapeutically to improve the in vivo function of adoptively transferred, tumor-reactive T cells for the treatment of cancer.

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“…Mice deficient in IL-21 receptor (IL-21R) have normal T cell and NK cell development and do not develop spontaneous autoimmune disease, suggesting a role for IL-21 that is distinct from that of IL-2 or IL-15 (5,6). IL-21R-deficient mice have deficits in humoral immunity (6), consistent with a nonredundant role for IL-21 in B cell responses. In addition, multiple studies indicate that IL-21 can potentiate antitumor responses, supporting a potential role for IL-21 as a proinflammatory cytokine (7)(8)(9).…”

mentioning

confidence: 99%

Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

Young¹,

Hegen²,

Margery³

et al. 2007

Arthritis & Rheumatism

256

203

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Objective. Interleukin-21 (IL-21) is a T cellderived cytokine that modulates T cell, B cell, and natural killer cell responses. In this study, the effects of blocking IL-21 were examined in 2 rodent models of rheumatoid arthritis (RA) to determine whether IL-21 contributes to their pathologic processes.Methods. DBA/1 mice were immunized with bovine type II collagen and then treated with murine IL-21 receptor Fc fusion protein (IL-21R.Fc), which was initiated after the onset of arthritis symptoms in 10% of the cohort. The mice were assessed 3 times per week for signs of disease, including histologic features as well as serum cytokine, Ig, and cytokine messenger RNA (mRNA) levels in the paws. In a separate experiment, Lewis rats were immunized with Freund's complete adjuvant followed by administration of IL-21R.Fc at the peak of inflammation in the joints. Rats were assessed daily for histologic features and for scoring of arthritis severity. In addition, the effects of IL-21R.Fc on the production of interferon-␥ (IFN␥) by T cells were examined.Results Conclusion. These findings demonstrate a pathogenic role for IL-21 in animal models of RA, and support consideration of IL-21 as a therapeutic target in human RA.

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A Critical Role for IL-21 in Regulating Immunoglobulin Production

Cited by 886 publications

References 29 publications

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

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

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

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