Kinetics of thymocyte subset development and selection revealed by cyclosporin A treatment.
Cyclosporin A (CsA) inhibits the development of mature thymocytes from their CD4+ CD8+ precursors, but may allow autoreactive cells to mature. Using 3-color flow cytometry, we have followed the progressive development of thymocytes, including potentially autoreactive cells, during CsA treatment. Numbers of CD4+ CD8+ CD3high thymocytes dropped immediately, suggesting that the generation of these mature thymocyte precursors, normally dependent upon positive selection, was inhibited by CsA. Numbers of CD4+ CD8- thymocytes also declined rapidly, but CD4 - CD8+ thymocytes were unaffected for 2 days, suggesting that the mature single-positive subsets are not symmetrically derived from a common GsA-sensitive precursor. An exceptional subset of CD8 SP thymocytes, expressing CD45RA, did not respond to CsA for about 10 days, indicating that they are distantly derived from a CsA-sensitive precursor. Apoptosis of TCR-V beta 3 + thymocytes caused by Mtv-6, quantified according to the down-regulation of CD4 and CD8 on immature thymocytes, was partially inhibited by CsA, to maximal effect within 24 hours. This did not, however, facilitate their development into mature thymocytes.
Huby
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RD
Imperial Cancer Research Fund, Human Tumour Immunology Group, Courtauld Institute for Biochemistry, London, UK.
Hicks
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Goff
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LK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007700:Kinetics; D018655:Lymphocyte Count / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism
D015704:CD4 Antigens; D016827:CD8 Antigens; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016572:Cyclosporine