title: IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Coquet
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kyparissoudis
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Pellicci
authors.forename: Gurdyal
authors.initials: G
authors.lastname: Besra
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Berzins
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism; D019898:Autocrine Communication / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005699:Galactosylceramides / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D053804:Granzymes / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D000950:Antigens, Ly; D016207:Cytokines; D005699:Galactosylceramides; D007378:Interleukins; C408248:Ly49I antigen; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011971:Receptors, Immunologic; C493154:alpha-galactosylceramide; D053804:Granzymes; D000098546:Interleukin-21