title: The Ikaros transcription factor regulates responsiveness to IL-12 and expression of IL-2 receptor alpha in mature, activated CD8 T cells.
abstract: The Ikaros family of transcription factors is critical for normal T cell development while limiting malignant transformation. Mature CD8 T cells express multiple Ikaros family members, yet little is known about their function in this context. To test the functions of this gene family, we used retroviral transduction to express a naturally occurring, dominant negative (DN) isoform of Ikaros in activated CD8 T cells. Notably, expression of DN Ikaros profoundly enhanced the competitive advantage of activated CD8 T cells cultured in IL-12, such that by 6 days of culture, DN Ikaros-transduced cells were 100-fold more abundant than control cells. Expression of a DN isoform of Helios, a related Ikaros-family transcription factor, conferred a similar advantage to transduced cells in IL-12. While DN Ikaros-transduced cells had higher expression of the IL-2 receptor alpha chain, DN Ikaros-transduced cells achieved their competitive advantage through an IL-2 independent mechanism. Finally, the competitive advantage of DN Ikaros-transduced cells was manifested in vivo, following adoptive transfer of transduced cells. These data identify the Ikaros family of transcription factors as regulators of cytokine responsiveness in activated CD8 T cells, and suggest a role for this family in influencing effector and memory CD8 T cell differentiation.
authors.affiliation: Integrated Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. eric.clambey@ucdenver.edu
authors.forename: Eric T
authors.initials: ET
authors.lastname: Clambey
authors.forename: Bernard
authors.initials: B
authors.lastname: Collins
authors.forename: Mary H
authors.initials: MH
authors.lastname: Young
authors.forename: Jens
authors.initials: J
authors.lastname: Eberlein
authors.forename: Alexandria
authors.initials: A
authors.lastname: David
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D018664:Interleukin-12