CD3-epsilon overexpressed in prothymocytes acts as an oncogene.
BACKGROUND
Upon engagement of the T cell receptor for antigen, its associated CD3 proteins recruit signal transduction molecules, which in turn regulate T lymphocyte proliferation, apoptosis, and thymocyte development. Because some signal transducing molecules recruited by CD3-epsilon, i.e., p56lck and p59fyn, are oncogenic and since we previously found that overexpression of CD3-epsilon transgenes causes a block in T lymphocyte and NK cell development, we tested the hypothesis that aberrant CD3-epsilon signaling leads both to abnormal T lymphocyte death and lymphomagenesis.


METHODS
Ten independently derived transgenic mouse lines were generated with four different genomic CD3-epsilon constructs. Mice either homozygous or hemizygous for each transgene were analyzed for an arrest in T lymphocyte development and for the occurrence of T cell lymphomas.


RESULTS
Aggressive clonal T cell lymphomas developed at very high frequencies in seven mouse lines with intermediate levels of copies of CD3-epsilon derived transgenes. However, these lymphomas were not found when high copy numbers of CD3-epsilon transgenes caused a complete block in early thymic development or when a transgene was used in which the exons coding for the CD3-epsilon protein were deleted. Analyses of a series of double mutant mice, tgCD3-epsilon x RAG-2null, indicated that lymphomagenesis was initiated in lineage-committed prothymocytes, i.e., before rearrangement of the T cell receptor genes. In addition, the transgene coding for the CD3-epsilon cytoplasmic domain and its transmembrane region induced a T cell differentiation signal in premalignant tgCD3-epsilon x RAG-2null mice.


CONCLUSIONS
The nonenzymatic CD3-epsilon protein acted as a potent oncogene when overexpressed early in T lymphocyte development. Lymphomagenesis was dependent on signal transduction events initiated by the cytoplasmic domain of CD3-epsilon.
Wang
B
B
Beth Israel Deaconess Medical Center, Division of Immunology, Boston, MA 02215, USA.
She
J
J
Salio
M
M
Allen
D
D
Lacy
E
E
Lonberg
N
N
Terhorst
C
C
D000818:Animals; D017252:CD3 Complex / Q000502:physiology*; D016923:Cell Death; D003593:Cytoplasm; D004268:DNA-Binding Proteins; D008198:Lymph Nodes / Q000473:pathology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D016399:Lymphoma, T-Cell / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes / Q000502:physiology*; D011506:Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology*; D013945:Thymoma; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development* / Q000473:pathology; D019061:src-Family Kinases / Q000502:physiology
D017252:CD3 Complex; D004268:DNA-Binding Proteins; D011506:Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases