title: IL-21 promotes CD8+ CTL activity via the transcription factor T-bet.
abstract: CD8(+) T cells are fundamental for immune-mediated clearance of viral infections and contribute to immune pathology in autoimmune diseases such as type 1 diabetes. To execute these functions, CD8(+) T cells must differentiate into CTLs, a process that is precisely regulated by a variety of cytokines, costimulatory molecules, and transcription factors. IL-21 is an IL-2 family cytokine and a growth factor for multiple lymphocyte effector lineages, including cytotoxic CD8(+) T cells. Recent studies demonstrate that loss of IL-21 signaling results in reduced viral clearance in models of lymphocytic choriomeningitis virus infection, and also protection from type 1 diabetes in the NOD model. This is most likely the result of impaired CD8(+) CTL function in the absence of IL-21 signaling. Currently, the mechanisms by which IL-21 promotes CTL differentiation in CD8(+) T cells remain unclear, particularly the identity of the relevant transcription factor(s). We show that IL-21 promotes CTL function in vitro and killing of pancreatic islets in vivo via the use of transgenic mice expressing IL-21 in pancreatic β cells. We demonstrate that IL-21 induces the expression of the transcription factor T-bet in CD8(+) T cells, predominantly via STAT1, and that T-bet is required for the induction of cytolytic molecules, including perforin and granzyme B in response to IL-21. Finally, we show that IL-21-induced CTL function is T-bet dependent, as T-bet deficiency results in defective IL-21-dependent cytotoxicity in CD8(+) T cells in vitro and in vivo. Thus, IL-21 drives CD8(+) CTL differentiation via the actions of the transcription factor T-bet.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. asutherland@svi.edu.au
authors.forename: Andrew P R
authors.initials: AP
authors.lastname: Sutherland
authors.forename: Nicole
authors.initials: N
authors.lastname: Joller
authors.forename: Monia
authors.initials: M
authors.lastname: Michaud
authors.forename: Sue M
authors.initials: SM
authors.lastname: Liu
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Grusby
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020825:T-Box Domain Proteins / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21