title: IL-21 promotes differentiation of naive CD8 T cells to a unique effector phenotype.
abstract: IL-21, the most recently described member of the common gamma-chain cytokine family, is produced by activated CD4 T cells, whereas CD8 T cells express the IL-21 receptor. To investigate a possible role for IL-21 in the priming of naive CD8 T cells, we examined responses of highly purified naive OT-I CD8 T cells to artificial APCs displaying Ag and B7-1 on their surface. We found that IL-21 enhanced OT-I clonal expansion and supported development of cytotoxic effector function. High levels of IL-2 did not support development of effector functions, but IL-2 was required for optimal responses in the presence of IL-21. IL-12 and IFN-alpha have previously been shown to support naive CD8 T cell differentiation and acquisition of effector functions through a STAT4-dependent mechanism. Here, we show that IL-21 does not require STAT4 to stimulate development of cytolytic activity. Furthermore, IL-21 fails to induce IFN-gamma or IL-4 production and can partially block IL-12 induction of IFN-gamma production. CD8 T cells that differentiate in response to IL-21 have a distinct surface marker expression pattern and are characterized as CD44(high), PD-1(low), CD25(low), CD134(low), and CD137(low). Thus, IL-21 can provide a signal required by naive CD8 T cells to differentiate in response to Ag and costimulation, and the resulting effector cells represent a unique effector phenotype with highly effective cytolytic activity, but deficient capacity to secrete IFN-gamma.
authors.affiliation: Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Casey
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Mescher
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000954:Antigens, Surface / Q000032:analysis / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation; D002462:Cell Membrane; D003602:Cytotoxicity, Immunologic; D016898:Interferon-alpha; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors; D007376:Interleukin-2 / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000098546:Interleukin-21
chemical_list: D000954:Antigens, Surface; D018122:B7-1 Antigen; D016898:Interferon-alpha; D007376:Interleukin-2; D007378:Interleukins; D050797:STAT4 Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma; D000098546:Interleukin-21