CD3-epsilon overexpressed in prothymocytes acts as an oncogene

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• T cell receptor (TCR) engagement activates CD3 proteins, regulating T lymphocyte functions.
• Aberrant signaling molecules recruited by CD3-epsilon, such as p56lck and p59fyn, are oncogenic.
• Previous studies linked CD3-epsilon transgene overexpression to blocked T and NK cell development.

Purpose of the Study:

• To investigate if aberrant CD3-epsilon signaling causes abnormal T lymphocyte death and lymphomagenesis.
• To test the hypothesis that CD3-epsilon acts as an oncogene.

Main Methods:

• Generated ten transgenic mouse lines with four distinct genomic CD3-epsilon constructs.
• Analyzed mice (homozygous or hemizygous) for T lymphocyte development arrest and T cell lymphomas.
• Utilized double mutant mice (tgCD3-epsilon x RAG-2null) to pinpoint the timing of lymphomagenesis initiation.

Main Results:

• High frequencies of aggressive T cell lymphomas observed in seven lines with intermediate CD3-epsilon transgene levels.
• Lymphomas were absent in lines with high transgene copy numbers (blocking early development) or deleted CD3-epsilon exons.
• Lymphomagenesis initiated in lineage-committed prothymocytes before T cell receptor gene rearrangement.
• CD3-epsilon cytoplasmic domain and transmembrane region induced T cell differentiation signals in premalignant mice.

Conclusions:

• Overexpressed CD3-epsilon functions as a potent oncogene in early T lymphocyte development.
• Lymphomagenesis is critically dependent on signal transduction events originating from the CD3-epsilon cytoplasmic domain.