Cross-lineage expression of Ig-beta (B29) in thymocytes: positive and negative gene regulation to establish T cell identity.
Developmental commitment involves activation of lineage-specific genes, stabilization of a lineage-specific gene expression program, and permanent inhibition of inappropriate characteristics. To determine how these processes are coordinated in early T cell development, the expression of T and B lineage-specific genes was assessed in staged subsets of immature thymocytes. T lineage characteristics are acquired sequentially, with germ-line T cell antigen receptor-beta transcripts detected very early, followed by CD3epsilon and terminal deoxynucleotidyl transferase, then pTalpha, and finally RAG1. Only RAG1 expression coincides with commitment. Thus, much T lineage gene expression precedes commitment and does not depend on it. Early in the course of commitment to the T lineage, thymocytes lose the ability to develop into B cells. To understand how this occurs, we also examined expression of well defined B lineage-specific genes. Although lambda5 and Ig-alpha are not expressed, the mu 0 and I mu transcripts from the unrearranged IgH locus are expressed early, in distinct patterns, then repressed just before RAG1 expression. By contrast, RNA encoding the B cell receptor component Ig-beta was found to be transcribed in all immature thymocyte subpopulations and throughout most thymocyte differentiation. Ig-beta expression is down-regulated only during positive selection of CD4(+)CD8(-) cells. Thus several key participants in the B cell developmental program are expressed in non-B lineage-committed cells, and one is maintained even through commitment to an alternative lineage, and repressed only after extensive T lineage differentiation. The results show that transcriptional activation of "lymphocyte-specific" genes can occur in uncommitted precursors, and that T lineage commitment is a composite of distinct positive and negative regulatory events.
Wang
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Stowers Institute for Medical Research, California Institute of Technology, Pasadena, CA 91125, USA.
Diamond
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RA
Rothenberg
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EV
D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D051925:CD79 Antigens; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics* / Q000276:immunology*; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D008099:Liver / Q000196:embryology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000196:embryology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
D015703:Antigens, CD; D051925:CD79 Antigens; C497884:Cd79b protein, mouse