title: 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.
abstract: 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.
authors.affiliation: Amgen Institute, University of Toronto, Canada.
authors.forename: V A
authors.initials: VA
authors.lastname: Wallace
authors.forename: K
authors.initials: K
authors.lastname: Kawai
authors.forename: C N
authors.initials: CN
authors.lastname: Levelt
authors.forename: K
authors.initials: K
authors.lastname: Kishihara
authors.forename: T
authors.initials: T
authors.lastname: Molina
authors.forename: E
authors.initials: E
authors.lastname: Timms
authors.forename: H
authors.initials: H
authors.lastname: Pircher
authors.forename: J
authors.initials: J
authors.lastname: Penninger
authors.forename: P S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: K
authors.initials: K
authors.lastname: Eichmann
mesh_terms: 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
chemical_list: D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)