| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Brady, Brenna L. Carpenter, Andrea C. Rupp, Levi J. Muljo, Stefan A. Bassing, Craig H. De Obaldia, Maria Elena Bhandoola, Avinash Bosselut, Remy |
| Description |
Author Affiliation: Rupp LJ ( Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104); Brady BL ( Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104); Carpenter AC ( Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892); De Obaldia ME ( Immunology Graduate Group, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.); Bhandoola A ( Immunology Graduate Group, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.); Bosselut R ( Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892); Muljo SA ( Integrative Immunobiology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Bassing CH ( Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104) |
| Abstract |
Differentiation of CD4(+) helper and CD8(+) cytotoxic ß T cells from CD4(+)CD8(+) thymocytes involves upregulation of lineage-specifying transcription factors and transcriptional silencing of CD8 or CD4 coreceptors, respectively, in MHC class II or I (MHCII or I)-restricted thymocytes. In this study, we demonstrate that inactivation of the Dicer RNA endonuclease in murine thymocytes impairs initiation of Cd4 and Cd8 silencing, leading to development of positively selected MHCI- and MHCII-restricted mature CD4(+)CD8(+) thymocytes. Expression of the antiapoptotic BCL2 protein or inactivation of the p53 proapoptotic protein rescues these thymocytes from apoptosis, increasing their frequency and permitting accumulation of CD4(+)CD8(+) ß T cells in the periphery. Dicer-deficient MHCI-restricted ß T cells fail to normally silence Cd4 and display impaired induction of the CD8 lineage-specifying transcription factor Runx3, whereas Dicer-deficient MHCII-restricted ß T cells show impaired Cd8 silencing and impaired induction of the CD4 lineage-specifying transcription factor Thpok. Finally, we show that the Drosha RNA endonuclease, which functions upstream of Dicer in microRNA biogenesis, also regulates Cd4 and Cd8 silencing. Our data demonstrate a previously dismissed function for the microRNA biogenesis machinery in regulating expression of lineage-specifying transcription factors and silencing of Cd4 and Cd8 during ß T cell differentiation. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| DOI |
10.4049/jimmunol.1401359 |
| Journal |
The Journal of Immunology |
| Issue Number |
8 |
| Volume Number |
193 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2014-10-15 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Dead-box Rna Helicases Genetics Micrornas Receptors, Antigen, T-cell, Alpha-beta Ribonuclease Iii T-lymphocytes, Cytotoxic Cytology T-lymphocytes, Helper-inducer Animals Antigens, Cd4 Immunology Antigens, Cd8 Apoptosis Cell Differentiation Cell Lineage Core Binding Factor Alpha 3 Subunit Histocompatibility Antigens Class I Histocompatibility Antigens Class Ii Mice Mice, Knockout Biosynthesis Proto-oncogene Proteins C-bcl-2 Transcription Factors Tumor Suppressor Protein P53 Metabolism Up-regulation Research Support, N.i.h., Extramural Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
