Cargando…

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...

Descripción completa

Detalles Bibliográficos
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 1996
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192768/
https://www.ncbi.nlm.nih.gov/pubmed/9064353
_version_ 1782147313570938880
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