IL-21 Is Produced by NKT Cells and Modulates NKT Cell Activation and Cytokine Production

• Published in: Journal of Immunology Vol. 178; no. 5; pp. 2827 - 2834
• Main Authors: Coquet, Jonathan M, Kyparissoudis, Konstantinos, Pellicci, Daniel G, Besra, Gurdyal, Berzins, Stuart P, Smyth, Mark J, Godfrey, Dale I
• Format: Journal Article
• Language: English
• Published: England Am Assoc Immnol 01.03.2007
• Subjects: 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; Interleukin-21; 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
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.5.2827

The common γ-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 α-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 α-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.