T lymphocyte development in p56lck deficient mice: allelic exclusion of the TcR beta locus is incomplete but thymocyte development is not restored by TcR beta or TcR alpha beta transgenes.
The protein tyrosine kinase, p56lck, is involved in signal transduction in mature T cells and in the molecular events controlling early thymocyte differentiation. Thymuses of mice deficient for p56lck expression (p56lck-/-) consist of immature CD4-CD8- double-negative (DN) and CD4+CD8+ double-positive (DP) thymocytes and are severely reduced in total cell number. In this report we have studied DN thymocytes from p56lck-/- mice and found an increase in the proportion of the CD44-CD25+ subset, suggesting that transit through this stage, which is known to require T cell receptor (TcR) beta expression, may be delayed in the absence of p56lck expression. In addition, the expression of a transgenic TcR beta chain or TcR alpha beta pair did not restore thymic development in p56lck-/- mice. However, in contrast to mice expressing a dominant negative isoform of p56lck in which DP thymocytes do not develop, DP thymocytes still develop in nontransgenic and TcR transgenic p56lck-/- mice. These results demonstrate that expansion of the DP subset is impaired in p56lck-/- mice. In contrast, allelic exclusion is not severely compromised. Although there was an increase in the number of peripheral T cells expressing more than one V beta chain in TcR transgenic p56lck-/- mice, we found that inhibition of endogenous TcR beta gene rearrangement was almost complete in thymocytes of V beta transgenic p56lck-/- mice and we could not detect any peripheral T cells that expressed more than one V beta chain in non-transgenic p56lck-/- mice.
Wallace
V A
VA
Amgen Institute, University of Toronto, Canada.
Kawai
K
K
Levelt
C N
CN
Kishihara
K
K
Molina
T
T
Timms
E
E
Pircher
H
H
Penninger
J
J
Ohashi
P S
PS
Eichmann
K
K
D000483:Alleles; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D015329:Gene Rearrangement, T-Lymphocyte; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008215:Lymphocytes, Null / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology
D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)