title: The impact of KLF2 modulation on the transcriptional program and function of CD8 T cells.
abstract: Krüppel-like factor 2 (KLF2) is a transcription factor that is highly expressed in quiescent T lymphocytes and downregulated in effector T cells. We now show that antigen receptor engagement downregulates KLF2 expression in a graded response determined by the affinity of T cell antigen receptor (TCR) ligand and the integrated activation of protein kinase B and the MAP kinases ERK1/2. The present study explores the importance of KLF2 downregulation and reveals that the loss of KLF2 controls a select portion of the CD8 effector T cell transcriptional program. In particular, KLF2 loss is required for CD8 T cells to express the inflammatory chemokine receptor CXCR3 and for maximum clonal expansion of T cells. KLF2 thus negatively controls the ability of CD8 T cells to respond to the CXCR3 ligand CXCL10. Strikingly, the KLF2 threshold for restraining expression of CXCR3 is very low and quite distinct to the KLF2 threshold for restraining T cell proliferation. KLF2 is thus an analogue (tunable) not a digital (on/off) cellular switch where the magnitude of KLF2 expression differentially modifies the T cell responses.
authors.affiliation: Department of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Preston
authors.forename: Carmen
authors.initials: C
authors.lastname: Feijoo-Carnero
authors.forename: Nick
authors.initials: N
authors.lastname: Schurch
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Cowling
authors.forename: Doreen A
authors.initials: DA
authors.lastname: Cantrell
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016207:Cytokines; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D011948:Receptors, Antigen, T-Cell; D054367:Receptors, CXCR3; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D020123:Sirolimus