TCR signal strength controls thymic differentiation of iNKT cell subsets
| Autor: | Kent Riemondy, Anjana Rao, Brian P. O'Connor, S. Harsha Krovi, Laurent Gapin, Adam R. Lefferts, Jay R. Hesselberth, Leonard L. Dragone, Catherine Halluszczak, Philippa Marrack, Jingjing Zhang, Lisa K. Peterson, Kathryn D. Tuttle, Laura Harmacek, James P. Scott-Browne, Romain Bedel |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Science Receptors Antigen T-Cell General Physics and Astronomy Mice Transgenic Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation T-Lymphocyte Subsets Animals Binding Sites Cell Differentiation/genetics Cell Differentiation/immunology Cells Cultured Early Growth Response Protein 2/genetics Early Growth Response Protein 2/immunology Early Growth Response Protein 2/metabolism Gene Expression Profiling/methods Mice Inbred BALB C Mice Inbred C57BL NFATC Transcription Factors/genetics NFATC Transcription Factors/immunology NFATC Transcription Factors/metabolism Natural Killer T-Cells/immunology Natural Killer T-Cells/metabolism Receptors Antigen T-Cell/genetics Receptors Antigen T-Cell/immunology Receptors Antigen T-Cell/metabolism Signal Transduction/genetics Signal Transduction/immunology T-Lymphocyte Subsets/immunology T-Lymphocyte Subsets/metabolism Thymocytes/cytology Thymocytes/immunology Thymocytes/metabolism Binding site Enhancer Receptor lcsh:Science Gene Early Growth Response Protein 2 Multidisciplinary Thymocytes NFATC Transcription Factors Gene Expression Profiling T-cell receptor NFAT Cell Differentiation General Chemistry Chromatin Cell biology 030104 developmental biology Natural Killer T-Cells lcsh:Q 030215 immunology Signal Transduction |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) Nature Communications Nature communications, vol. 9, no. 1, pp. 2650 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-05026-6 |
| Popis: | During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets, with strong signaling promoting iNKT2 and iNKT17 development. Altering TCR diversity or signaling diminishes iNKT2 and iNKT17 cell subset development in a cell-intrinsic manner. Decreased TCR signaling affects the persistence of Egr2 expression and the upregulation of PLZF. By genome-wide comparison of chromatin accessibility, we identify a subset of iNKT2-specific regulatory elements containing NFAT and Egr binding motifs that is less accessible in iNKT2 cells that develop from reduced TCR signaling. These data suggest that variable TCR signaling modulates regulatory element activity at NFAT and Egr binding sites exerting a determinative influence on the dynamics of gene enhancer accessibility and the developmental fate of iNKT cells. Invariant natural killer T (iNKT) cells can be subsetted by their cytokine profiles, but how they develop in the thymus is unclear. Here the authors show, by analysing mice carrying mutant Zap70 genes, that T cell receptor signaling strength induces epigenetic changes of genes to modulate iNKT lineages. |
| Databáze: | OpenAIRE |
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