IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production

J Immunol. 2007 Mar 1;178(5):2827-34. doi: 10.4049/jimmunol.178.5.2827.


The common gamma-chain cytokine, IL-21, is produced by CD4(+) T cells and mediates potent effects on a variety of immune cells including NK, T, and B cells. NKT cells express the receptor for IL-21; however, the effect of this cytokine on NKT cell function has not been studied. We show that IL-21 on its own enhances survival of NKT cells in vitro, and IL-21 increases the proliferation of NKT cells in combination with IL-2 or IL-15, and particularly with the CD1d-restricted glycosphingolipid Ag alpha-galactosylceramide. Similar to its effects on NK cells, IL-21 enhances NKT cell granular morphology, including granzyme B expression, and some inhibitory NK receptors, including Ly49C/I and CD94. IL-21 also enhanced NKT cell cytokine production in response to anti-CD3/CD28 in vitro. Furthermore, NKT cells may be subject to autocrine IL-21-mediated stimulation because they are potent producers of this cytokine following in vitro stimulation via CD3 and CD28, particularly in conjunction with IL-12 or following in vivo stimulation with alpha-galactosylceramide. Indeed, NKT cells produced much higher levels of IL-21 than conventional CD4 T cells in this assay. This study demonstrates that NKT cells are potentially a major source of IL-21, and that IL-21 may be an important factor in NKT cell-mediated immune regulation, both in its effects on NK, T, and B cells, as well as direct effects on NKT cells themselves. The influence of IL-21 in NKT cell-dependent models of tumor rejection, microbial clearance, autoimmunity, and allergy should be the subject of future investigations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / immunology
  • Antigens, Ly / metabolism
  • Autocrine Communication / immunology*
  • B-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Survival / immunology
  • Cytokines / immunology
  • Galactosylceramides / immunology
  • Gene Expression Regulation, Enzymologic / immunology
  • Granzymes / biosynthesis
  • Granzymes / immunology
  • Interleukins / biosynthesis
  • Interleukins / immunology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation / immunology*
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily D / immunology
  • NK Cell Lectin-Like Receptor Subfamily D / metabolism
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism


  • Antigens, Ly
  • Cytokines
  • Galactosylceramides
  • Interleukins
  • Ly49I antigen
  • NK Cell Lectin-Like Receptor Subfamily D
  • Receptors, Immunologic
  • alpha-galactosylceramide
  • Granzymes
  • interleukin-21