Mislocalization of Lck impairs thymocyte differentiation and can promote development of thymomas.
T-cell development is critically dependent on the activities of the Src-family kinases p56(lck) and p59(fyn). While Lck plays a dominant role in the initiation of T-cell receptor (TCR) signaling and in thymocyte differentiation, Fyn plays a more subtle regulatory role. We sought to determine the role of intracellular localization in the differing functions of Lck and Fyn in T cells. By generating transgenic mice that express chimeric Lck-Fyn proteins, we showed that the N-terminal unique domain determines the intracellular localization and function of Lck in pre-TCR and mature αβTCR signaling in vivo. Furthermore, coexpression of a "domain-swap" Lck protein containing the Fyn unique domain with an inducible Lck transgene resulted in the development of thymomas. In contrast to previous reports of Lck-driven thymomas, tumor development was dependent on either pre-TCR or mature TCR signals, and was completely ablated when mice were crossed to a recombination activating gene 1 (Rag1)-deficient background. These data provide a mechanistic basis for the differing roles of Lck and Fyn in T-cell development, and show that intracellular localization as determined by the N-terminal unique domains is critical for Src-family kinase function in vivo.
Salmond
Robert J
RJ
Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
Filby
Andrew
A
Pirinen
Niina
N
Magee
Anthony I
AI
Zamoyska
Rose
R
D000818:Animals; D015153:Blotting, Western; D018801:CD2 Antigens / Q000235:genetics; D002454:Cell Differentiation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D051076:Proto-Oncogene Proteins c-fyn / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013945:Thymoma / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism
D018801:CD2 Antigens; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C494960:Fyn protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn