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Orchestration of B and T cell responses in health and disease by common gamma chain family cytokines with a focus on IL-21

Members of a subfamily of the type 1 four-helix-bundle cytokines with receptors sharing the common gamma (cγ) chain including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 have distinct activities on the differentiation of effector, memory, and regulatory T cells [1, 2]. Furthermore, IL-2, IL-4, and IL-21 serve distinct roles in control of B cell development and differentiation to antibody producing cells. We and others recently reported that both IL-2 and IL-21 are essential for maintenance of CD8 T cells and control of chronic viral infection, while both cytokines are dispensable for expansion and contraction of CD8 T cells during acute and resolved viral infection [37].

While IL-21 has been implicated in cross-regulation of Th17 cells and inducible regulatory T cells (Treg) in vitro, development of Th17 and Treg cells and consequently organ-related autoimmune disease remain unaffected in IL-21R-deficient mice in vivo [8, 9]. In contrast, we now found that IL-21 can potently inhibit proliferation and function of inducible and natural Treg cells in models of T cell transfer colitis, viral infection, and asthma. Increased numbers of Tregs in IL-21R-deficient mice offer an explanation for suppression of Th2-mediated asthma and susceptibility to chronic viral infection described in the knockout mice [5, 10].

Furthermore, the importance of IL-21 for B cell and antibody responses has been well established. Recently, it has been suggested that IL-21 is crucial for development of T follicular helper cells (Tfh) and defective B cell responses in IL-21R-deficient mice are due to the absence of Tfh cells. However, we found that germinal center development and antibody responses were severely impaired in mice that lack IL-21R specifically on B cells suggesting that IL-21 regulates germinal center responses in a B cell intrinsic manner [11]. In addition, we have shown that requirement of IL-21 for a B cell response is overcome by immunization with particulate antigens containing TLR7/8 ligands (such as viral RNS). These data demonstrate that innate pathogen patterns (PAMPs) and Th cell derived signals co-operate in the induction of optimal IgG responses. Interestingly, in contrast to follicular B cell responses, IL-21 has been shown to negatively regulate marginal zone (MZ) B-cell survival and antibody production to Streptococous pneumonia [12].


  1. 1.

    Rochman Y, Spolski R, Leonard WJ: New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009, 9: 480-490. 10.1038/nri2580.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  2. 2.

    Spolski R, Leonard WJ: Interleukin-21: basic biology and implications for cancer and autoimmunity. Annual review of immunology. 2008, 26: 57-79. 10.1146/annurev.immunol.26.021607.090316.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Bachmann MF, Wolint P, Walton S, Schwarz K, Oxenius A: Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. European journal of immunology. 2007, 37: 1502-1512. 10.1002/eji.200637023.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Elsaesser H, Sauer K, Brooks DG: IL-21 is required to control chronic viral infection. Science. 2009, 324: 1569-1572. 10.1126/science.1174182.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  5. 5.

    Fröhlich A: IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science. 2009, 324: 1576-1580. 10.1126/science.1172815.

    Article  PubMed  Google Scholar 

  6. 6.

    Williams MA, Tyznik AJ, Bevan MJ: Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 2006, 441: 890-893. 10.1038/nature04790.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  7. 7.

    Yi JS, Zajac AJ: A vital role for interleukin-21 in the control of a chronic viral infection. Science. 2009, 324: 1572-1576. 10.1126/science.1175194.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  8. 8.

    Coquet JM, Chakravarti S, Smyth MJ, Godfrey DI: Cutting edge: IL-21 is not essential for Th17 differentiation or experimental autoimmune encephalomyelitis. J Immunol. 2008, 180: 7097-7101.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Sonderegger I, Kisielow J, Meier R, King C, Kopf M: IL-21 and IL-21R are not required for development of Th17 cells and autoimmunity in vivo. European journal of immunology. 2008, 38: 1833-1838. 10.1002/eji.200838511.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Fröhlich A: IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. Blood. 2007, 109: 2023-2031. 10.1182/blood-2006-05-021600.

    Article  PubMed  Google Scholar 

  11. 11.

    Bessa J, Kopf M, Bachmann MF: Cutting Edge: IL-21 and TLR Signaling Regulate Germinal Center Responses in a B Cell-Intrinsic Manner. J Immunol. 2010, 1-6.

    Google Scholar 

  12. 12.

    Tortola L: IL-21 induces death of marginal zone B cells during chronic inflammation. Blood. 2010, 116: 5200-5207. 10.1182/blood-2010-05-284547.

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Manfred Kopf.

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Kopf, M., Tortola, L., Schmitz, I. et al. Orchestration of B and T cell responses in health and disease by common gamma chain family cytokines with a focus on IL-21. Arthritis Res Ther 13, O9 (2011).

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  • Treg Cell
  • Germinal Center
  • Chronic Viral Infection
  • Gamma Chain
  • Antibody Produce Cell