Sustained expression of pre-TCR induced beta-catenin in post-beta-selection thymocytes blocks T cell development.
Pre-TCR and IL-7R signals regulate beta-selection of thymocytes and then must be down-regulated for further development. However, the molecular events that control down-regulation remain unknown. We and others have previously shown that beta-catenin in cooperation with TCF regulates beta-selection. In this paper, we demonstrate that beta-catenin expression is stringently regulated by intrathymic signals, it is expressed at the highest levels in the pre-TCR signaled thymocytes, and is down-regulated in post-beta-selection thymocytes. Pre-TCR-induced beta-catenin regulates initial stages of pre-TCR signaling including expression of early growth response (Egr) genes but must be down-regulated to express RORgammat, which is essential for maturation to the CD4+CD8+ double positive (DP) stage. Sustained expression of beta-catenin results in the generation of IL-7R-, Egr-, and TGFbeta-expressing pre-DP thymocytes that are blocked in development. These data are consistent with a model in which post-beta-selection, pre-TCR-induced beta-catenin expression must return to background levels for efficient transition to the DP stage.
Xu
Mai
M
Lymphocyte Development Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Sharma
Archna
A
Hossain
M Zulfiquer
MZ
Wiest
David L
DL
Sen
Jyoti Misra
JM
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000276:immunology*; D006131:Growth Inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011498:Protein Precursors / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
C495267:CTNNB1 protein, mouse; D006131:Growth Inhibitors; D011498:Protein Precursors; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051176:beta Catenin