Over-expression of CD3{varepsilon} transgenes blocks T lymphocyte development |
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Authors: | Wang, Baoping Levelt, Christiaan Salio, Mariolina Zheng, Dexian Sancho, Jaime Liu, Chih-Pin She, Jian Huang, Manley Higgins, Kay Sunshine, Mary-Jean Eichmann, Klaus Lacy, Elizabeth Lonberg, Nils Terhorst, Cox |
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Affiliation: | Division of Immunology, Beth Israel Hospital, Harvard Medical School Boston, MA 02115, USA 1 Max-Planck-Institut fur Immunbiologie Postfach, Freiburg, Germany 2 GenPharm International Mountain View, CA 94043, USA 3 DeWitt Wallace Research Laboratory, Program in Molecular Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center New York, NY 10021, USA |
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Abstract: | We have reported previously that mice carrying >30 copiesof the human CD3 transgene completely lose their T lymphocytesand NK cells (36). Here we demonstrate by immunohistology thatin the most severely immunodeficient mouse, tg26, the thymusis very small, has sizeable vacuoles and does not contain recognizableT lymphocytes except for a small percentage of Thy- 1+ cellsand B cells. Cell surface phenotyping and TCR and -ßrearrangement studies confirm that the arrest in T lymphocytedevelopment precedes the arrest in rag-1null, rag-2null andTCRßnull mice. Since the T cell progenitors in whichthe arrest occurred were absent in the transgenic mice, indirectapproaches were taken to examine the causes of the block inT cell development. Analyses of 12 independently establishedmutant mouse lines, generated with five different transgenicconstructs, revealed that the severity of the abrogation inT cell development was dependent on the number of copies oftransgenes. Since the number of transgene copies generally correlatedwith the levels of expression of the transgenic CD3 proteins,we concluded that over-expression of the CD3 protein was thelikely cause of the block in T lymphocyte development. The Tcell immunodeficiency was caused by either the human or themurine CD3 protein. Since transgene coded mRNAs were found insignificantly higher quantities than endogenous CD3 mRNAs infetal thymi on days 13 and 14 of gestation, over-expressiontook place very early in development, probably prematurely.Over-expression of the CD3 transgene in thymocyte precursorsmay therefore affect T lymphocyte development in the absenceof TCR and possibly in the absence of the other CD3 proteins.More importantly, over-expression of the CD3 protein in thymocytesof mice with a low copy number of transgenes had a significanteffect on late thymic development Over-expression of the CD3protein in immature thymocytes mimicked the effects caused byexposure of CD4–; CD8– thymocytes to anti-CD3 treatment:apoptosis and lack of TCRß expression. We thereforespeculate that in the homozygous tg26 animals the arrest inT cell development was caused by excessive signal transductionevents rather than by a toxic effect of the transgenic protein. |
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Keywords: | apoptosis over-expression of CD3 /math/epsiv.gif" ALT=" {varepsilon}" BORDER=" 0" > transgenic mice |
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