Abstract
BackgroundThe Tec-family kinase Itk plays an important role during T-cell activation and function, and controls also conventional versus innate-like T-cell development. We have characterized the transcriptome of Itk-deficient CD3+ T-cells, including CD4+ and CD8+ subsets, using Affymetrix microarrays.ResultsThe largest difference between Itk-/- and Wt CD3+ T-cells was found in unstimulated cells, e.g. for killer cell lectin-like receptors. Compared to anti-CD3-stimulation, anti-CD3/CD28 significantly decreased the number of transcripts suggesting that the CD28 co-stimulatory pathway is mainly independent of Itk. The signatures of CD4+ and CD8+ T-cell subsets identified a greater differential expression than in total CD3+ cells. Cyclosporin A (CsA)-treatment had a stronger effect on transcriptional regulation than Itk-deficiency, suggesting that only a fraction of TCR-mediated calcineurin/NFAT-activation is dependent on Itk. Bioinformatic analysis of NFAT-sites of the group of transcripts similarly regulated by Itk-deficiency and CsA-treatment, followed by chromatin-immunoprecipitation, revealed NFATc1-binding to the Bub1, IL7R, Ctla2a, Ctla2b, and Schlafen1 genes. Finally, to identify transcripts that are regulated by Tec-family kinases in general, we compared the expression profile of Itk-deficient T-cells with that of Btk-deficient B-cells and a common set of transcripts was found.ConclusionTaken together, our study provides a general overview about the global transcriptional changes in the absence of Itk.
Highlights
The Tec-family kinase Itk plays an important role during T-cell activation and function, and controls conventional versus innate-like T-cell development
The Tec family of non-receptor protein-tyrosine kinases consists of five members (Bmx, Btk, Itk, Rlk/Txk and Tec); T-cells express Itk, Rlk and Tec, and T-cell receptor (TCR)
More recent data indicate that Itk is involved in signaling pathways that regulate conventional versus innate-like T-cell development
Summary
The Tec-family kinase Itk plays an important role during T-cell activation and function, and controls conventional versus innate-like T-cell development. The majority of CD8+ T-cells from Itk-/- as well as from Itk-/-Rlk-/- mice show a more "innate-like" T-cell phenotype, sharing characteristics with conventional memory T-cells, i.e. CD44hi, CD62L- and CD122hi [9,10,11]. These cells depend on IL-15, express TCRs specific for non-classical MHC class Ib molecules, and exhibit direct effector functions such as rapid IFNγ production upon PMA/ionomycin stimulation [912]. A significant fraction of innate-like CD44hiCD62L- Tcells has been described for the CD4+ T-cell lineage in Itk-/- mice [13]
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