Exclusion and inclusion of TCR alpha proteins during T cell development in TCR-transgenic and normal mice.
Allelic exclusion of immune receptor genes (and molecules) is incompletely understood. With regard to TCRalphabeta lineage T cells, exclusion at the tcr-b, but not tcr-a, locus seems to be strictly controlled at the locus rearrangement level. Consequently, while nearly all developing TCRalphabeta thymocytes express a single TCRbeta protein, many thymocytes rearrange and express two different TCRalpha chains and, thus, display two alphabetaTCRs on the cell surface. Of interest, the number of such dual TCR-expressing cells is appreciably lower among the mature T cells. To understand the details of TCR chain regulation at various stages of T cell development, we analyzed TCR expression in mice transgenic for two rearranged alphabetaTCR. We discovered that in such TCR double-transgenic (TCRdTg) mice peripheral T cells were functionally monospecific. Molecularly, this monospecificity was due to TCRalpha exclusion: one transgenic TCRalpha protein was selectively down-regulated from the thymocyte and T cell surface. In searching for the mechanism(s) governing this selective TCRalpha down-regulation, we present evidence for the role of protein tyrosine kinase signaling and coreceptor involvement. This mechanism may be operating in normal thymocytes.
Lacorazza
H Daniel
HD
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Nikolich-Zugich
Janko
J
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005260:Female; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D005799:Genes, Dominant; D019673:Genes, T-Cell Receptor alpha; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*
D016693:Receptors, Antigen, T-Cell, alpha-beta; D011505:Protein-Tyrosine Kinases