ABSTRACT
ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Homeodomain Proteins/immunology , Lymphocytic Choriomeningitis/immunology , Repressor Proteins/immunology , T-Lymphocyte Subsets/immunology , Animals , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation/immunology , Flow Cytometry , Homeodomain Proteins/genetics , Host-Pathogen Interactions/immunology , Humans , Immunologic Memory/immunology , Lectins, C-Type , Lymphocytic Choriomeningitis/genetics , Lymphocytic Choriomeningitis/virology , Lymphocytic choriomeningitis virus/immunology , Lymphocytic choriomeningitis virus/physiology , Male , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Oligonucleotide Array Sequence Analysis , Protein Binding/immunology , Receptors, Immunologic/immunology , Receptors, Immunologic/metabolism , Repressor Proteins/deficiency , Repressor Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , T-Box Domain Proteins/immunology , T-Lymphocyte Subsets/metabolism , Transcriptome/genetics , Transcriptome/immunology , Zinc Finger E-box Binding Homeobox 2ABSTRACT
Cytolytic activity by CD8(+) cytotoxic T lymphocytes (CTLs) is a powerful strategy for the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTLs is progressively dampened during chronic infection, yet the environmental cues and molecular pathways that influence immunological 'exhaustion' remain unclear. Here we found that CTL immunity was regulated by the central transcriptional response to hypoxia, which is controlled in part by hypoxia-inducible factors (HIFs) and the von Hippel-Lindau tumor suppressor VHL. Loss of VHL, the main negative regulator of HIFs, led to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTLs displayed enhanced control of persistent viral infection and neoplastic growth. We found that HIFs and oxygen influenced the expression of pivotal transcription, effector and costimulatory-inhibitory molecules of CTLs, which was relevant to strategies that promote the clearance of viruses and tumors.
