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Requirement for p56lck tyrosine kinase activation in T cell receptor- mediated thymic selection
The nonreceptor protein tyrosine kinase p56lck (Lck) serves as a fundamental regulator of thymocyte development by delivering signals from the pre-T cell receptor (pre-TCR) that permit subsequent maturation. However, considerable evidence supports the view that Lck also participates in signal transd...
Formato: | Texto |
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Lenguaje: | English |
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The Rockefeller University Press
1996
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192768/ https://www.ncbi.nlm.nih.gov/pubmed/9064353 |
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collection | PubMed |
description | The nonreceptor protein tyrosine kinase p56lck (Lck) serves as a fundamental regulator of thymocyte development by delivering signals from the pre-T cell receptor (pre-TCR) that permit subsequent maturation. However, considerable evidence supports the view that Lck also participates in signal transduction from the mature TCR. We have tested this conjecture by expressing a dominant-negative form of Lck under the control of a promoter element (the distal lck promoter) that directs high expression in CD4+CD8+ thymocytes, mature thymocytes, and peripheral T cells, thereby avoiding, complications that result from the well-documented ability of dominant-negative Lck to block very early events in thymocyte maturation. Here we report that expression of the catalytically inactive Lck protein at twice normal concentrations inhibits thymocyte positive selection by as much as 80%, while leaving other aspects of cell maturation intact. This effect was studied in more detail in mice simultaneously bearing the male-specific H-Y alpha/beta TCR transgene and ovalbumin-specific DO10 alpha/beta TCR transgene, where even equimolar expression of the dominant-negative Lck protein substantially vitiated the positive selection process. Although deletion of H-Y alpha/beta thymocytes proceeded normally in male mice despite the presence of catalytically inactive Lck, modest inhibition of superantigen-mediated deletion was in some cases observed. These data further implicate Lck in the propagation of all TCR-derived signals, and indicate that even very modest deficiencies in the representation of functional Lck molecules could in humans, profoundly alter the character of the peripheral TCR repertoire. |
format | Text |
id | pubmed-2192768 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 1996 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21927682008-04-16 Requirement for p56lck tyrosine kinase activation in T cell receptor- mediated thymic selection J Exp Med Articles The nonreceptor protein tyrosine kinase p56lck (Lck) serves as a fundamental regulator of thymocyte development by delivering signals from the pre-T cell receptor (pre-TCR) that permit subsequent maturation. However, considerable evidence supports the view that Lck also participates in signal transduction from the mature TCR. We have tested this conjecture by expressing a dominant-negative form of Lck under the control of a promoter element (the distal lck promoter) that directs high expression in CD4+CD8+ thymocytes, mature thymocytes, and peripheral T cells, thereby avoiding, complications that result from the well-documented ability of dominant-negative Lck to block very early events in thymocyte maturation. Here we report that expression of the catalytically inactive Lck protein at twice normal concentrations inhibits thymocyte positive selection by as much as 80%, while leaving other aspects of cell maturation intact. This effect was studied in more detail in mice simultaneously bearing the male-specific H-Y alpha/beta TCR transgene and ovalbumin-specific DO10 alpha/beta TCR transgene, where even equimolar expression of the dominant-negative Lck protein substantially vitiated the positive selection process. Although deletion of H-Y alpha/beta thymocytes proceeded normally in male mice despite the presence of catalytically inactive Lck, modest inhibition of superantigen-mediated deletion was in some cases observed. These data further implicate Lck in the propagation of all TCR-derived signals, and indicate that even very modest deficiencies in the representation of functional Lck molecules could in humans, profoundly alter the character of the peripheral TCR repertoire. The Rockefeller University Press 1996-09-01 /pmc/articles/PMC2192768/ /pubmed/9064353 Text en This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Articles Requirement for p56lck tyrosine kinase activation in T cell receptor- mediated thymic selection |
title | Requirement for p56lck tyrosine kinase activation in T cell receptor- mediated thymic selection |
title_full | Requirement for p56lck tyrosine kinase activation in T cell receptor- mediated thymic selection |
title_fullStr | Requirement for p56lck tyrosine kinase activation in T cell receptor- mediated thymic selection |
title_full_unstemmed | Requirement for p56lck tyrosine kinase activation in T cell receptor- mediated thymic selection |
title_short | Requirement for p56lck tyrosine kinase activation in T cell receptor- mediated thymic selection |
title_sort | requirement for p56lck tyrosine kinase activation in t cell receptor- mediated thymic selection |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192768/ https://www.ncbi.nlm.nih.gov/pubmed/9064353 |