Upregulation of CD4 expression during MHC class II-specific positive selection is essential for error-free lineage choice.
The lineage fate of developing thymocytes is determined by the persistence or cessation of T cell receptor (TCR) signaling during positive selection, with persistent TCR signaling required for CD4 lineage choice. We show here that transcriptional upregulation of CD4 expression is essential for error-free lineage choice during major histocompatibility complex class II (MHC II)-specific positive selection and is critical for error-free lineage choice in TCR-transgenic mice whose thymocytes compete for the identical selecting ligand. CD4 upregulation occurred for endogenously encoded CD4 coreceptors, but CD4 transgenes were downregulated during positive selection, disrupting MHC II-specific TCR signaling and causing lineage errors regardless of the absolute number or signaling strength of transgenic CD4 proteins. Thus, the kinetics of CD4 coreceptor expression during MHC II-specific positive selection determines the integrity of CD4 lineage choice, revealing an elegant symmetry between coreceptor kinetics and lineage choice.
Sarafova
Sophia D
SD
Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Van Laethem
Francois
F
Adoro
Stanley
S
Guinter
Terry
T
Sharrow
Susan O
SO
Feigenbaum
Lionel
L
Singer
Alfred
A
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D019070:Cell Lineage; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
D015704:CD4 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; C493730:Runx3 protein, mouse