title: Endogenous IL-21 restricts CD8+ T cell expansion and is not required for tumor immunity.
abstract: IL-21 has antitumor activity through actions on NK cells and CD8(+) T cells, and is currently in clinical development for the treatment of cancer. However, no studies have addressed the role of endogenous IL-21 in tumor immunity. In this study, we have studied both primary and secondary immune responses in IL-21(-/-) and IL-21R(-/-) mice against several experimental tumors. We found intact immune surveillance toward methylcholanthrene-induced sarcomas in IL-21(-/-) and IL-21R(-/-) mice compared with wild-type mice and B16 melanomas showed equal growth kinetics and development of lung metastases. IL-21R(-/-) mice showed competent NK cell-mediated rejection of NKG2D ligand (Rae1beta) expressing H-2b(-) RMAS lymphomas and sustained transition to CD8(+) T cell-dependent memory against H-2b(+) RMA lymphomas. alpha-Galactosylceramide stimulation showed equal expansion and activation of NKT and NK cells and mounted a powerful antitumor response in the absence of IL-21 signaling, despite reduced expression of granzyme B in NKT, NK, and CD8(+) T cells. Surprisingly, host IL-21 significantly restricted the expansion of Ag-specific CD8(+) T cells and inhibited primary CD8(+) T cell immunity against OVA-expressing EG7 lymphomas, as well as the secondary expansion of memory CD8(+) T cells. However, host IL-21 did not alter the growth of less immunogenic MC38 colon carcinomas with dim OVA expression. Overall, our results show that endogenous IL-21/IL-21R is not required for NK, NKT, and CD8(+) T cell-mediated tumor immunity, but restricts Ag-specific CD8(+) T cell expansion and rejection of immunogenic tumors, indicating novel immunosuppressive actions of this cytokine.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Henrik
authors.initials: H
authors.lastname: Søndergaard
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Coquet
authors.forename: Adam P
authors.initials: AP
authors.lastname: Uldrich
authors.forename: Nicole
authors.initials: N
authors.lastname: McLaughlin
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Pallavur V
authors.initials: PV
authors.lastname: Sivakumar
authors.forename: Kresten
authors.initials: K
authors.lastname: Skak
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007157:Immunologic Surveillance / Q000276:immunology*; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology*; D053655:Receptors, Interleukin-21 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21