c-Myb regulates lineage choice in developing thymocytes via its target gene Gata3.
During T-cell development, thymocytes with intermediate avidity for antigen-MHC complexes are positively selected and then differentiate into functional cytotoxic and helper T cells. This process is controlled by signalling from the T-cell receptor (TCR). Here, we show that the c-Myb transcription factor is a critical downstream regulator of positive selection, promoting the development of helper T cells and blocking the development of cytotoxic T cells. A gain-of-function c-Myb transgene stops development of cytotoxic T cells, instead causing accumulation of a precursor population. Conversely, loss of c-Myb in selecting cells results in significantly fewer helper T cells. In c-Myb-null thymocytes, Gata3, a critical inducer of T-helper cell fate, is not upregulated in response to T-cell receptor signaling, following selection. We show that Gata3 is a direct target of c-Myb, and propose that c-Myb is an important regulator of Gata3, required for transduction of the T-cell receptor signal for subsequent helper cell lineage differentiation.
Maurice
Diane
D
Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, London, UK.
Hooper
Joel
J
Lang
Georgina
G
Weston
Kathleen
K
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D002478:Cells, Cultured; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D051379:Mice; D020598:Proto-Oncogene Proteins c-myb / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology*
D017931:DNA Primers; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D020598:Proto-Oncogene Proteins c-myb; D011948:Receptors, Antigen, T-Cell