Ikaros imposes a barrier to CD8+ T cell differentiation by restricting autocrine IL-2 production.
Naive CD4(+) T cells require signals from the TCR and CD28 to produce IL-2, expand, and differentiate. However, these same signals are not sufficient to induce autocrine IL-2 production by naive CD8(+) T cells, which require cytokines provided by other cell types to drive their differentiation. The basis for failed autocrine IL-2 production by activated CD8(+) cells is unclear. We find that Ikaros, a transcriptional repressor that silences IL-2 in anergic CD4(+) T cells, also restricts autocrine IL-2 production by CD8(+) T cells. We find that CD8(+) T cell activation in vitro in the absence of exogenous cytokines and CD4 help leads to marked induction of Ikaros, a known repressor of the Il2 gene. Naive murine CD8 T cells haplo-insufficient for Ikzf1 failed to upregulate Ikaros, produced autocrine IL-2, and differentiated in an IL-2-dependent manner into IFN-γ-producing CTLs in response to TCR/CD28 stimulation alone. Furthermore, Ikzf1 haplo-insufficient CD8(+) T cells were more effective at controlling Listeria infection and B16 melanoma growth in vivo, and they could provide help to neighboring, non-IL-2-producing cells to differentiate into IFN-γ-producing effectors. Therefore, by repressing autocrine IL-2 production, Ikaros ensures that naive CD8(+) T cells remain dependent on licensing by APCs and CD4(+) T cells, and it may therefore act as a cell-intrinsic safeguard against inappropriate CTL differentiation and immunopathology.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Shaun
S
O'Brien
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104; and.
Rajan M
RM
Thomas
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104; and.
Gerald B
GB
Wertheim
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Fuqin
F
Zhang
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Hao
H
Shen
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104; and adwells@mail.med.upenn.edu.
Andrew D
AD
Wells
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology; D019898:Autocrine Communication / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D007376:Interleukin-2; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor