Delayed thymocyte development induced by augmented expression of p56lck.
Accumulating evidence supports the contention that CD4 and CD8 receptor molecules play a critical signaling role during thymocyte development. The lymphocyte-specific protein tyrosine kinase (p56lck), by virtue of its physical association with these surface components, provides a likely candidate for the biochemical signal transducing element required for these effects. To investigate the function of p56lck in T lymphocytes, transgenic mice were produced that carry either the wild-type lck gene or a mutated lck gene encoding a constitutively activated form of p56lck (p56lckF505). Both transgenes were expressed in thymocytes under the control of the lck proximal promoter element. A large set of founder animals was obtained in which steady-state accumulation of lck transgene mRNA directly correlated with transgene copy number, suggesting that this transgene contains a dominant control region. Progeny of these founders exhibited a transgene-dependent dose-related decrease in the production of thymocytes bearing functional antigen receptors. This effect was strictly dependent on p56lck activity, in that both wild-type and mutated versions of the genes induced similar effects with differing efficiencies. Remarkably, even a twofold increase in p56lck abundance was sufficient to substantially disrupt the appearance of functional thymocytes. These results indicate that thymocyte maturation is regulated in part by signals derived from p56lck.
Abraham
K M
KM
Howard Hughes Medical Institute, University of Washington, Seattle 98195.
Levin
S D
SD
Marth
J D
JD
Forbush
K A
KA
Perlmutter
R M
RM
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D017252:CD3 Complex; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens; D002454:Cell Differentiation; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006410:Hematopoiesis; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D008822:Mice, Transgenic; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)