International Immunology, Vol. 7, No. 3, pp. 435-448,March 1995
© 1995 Japanese Society for Immunology
Over-expression of CD3
transgenes blocks T lymphocyte development
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
Correspondence to: Correspondence to: C. Terhorst
We have reported previously that mice carrying >30 copies of the human CD3
transgene completely lose their T lymphocytes and NK cells (36). Here we demonstrate by immunohistology that in the most severely immunodeficient mouse, tg26, the thymus is very small, has sizeable vacuoles and does not contain recognizable T lymphocytes except for a small percentage of Thy- 1+ cells and B cells. Cell surface phenotyping and TCR
and -ß rearrangement studies confirm that the arrest in T lymphocyte development precedes the arrest in rag-1null, rag-2null and TCRßnull mice. Since the T cell progenitors in which the arrest occurred were absent in the transgenic mice, indirect approaches were taken to examine the causes of the block in T cell development. Analyses of 12 independently established mutant mouse lines, generated with five different transgenic constructs, revealed that the severity of the abrogation in T cell development was dependent on the number of copies of transgenes. Since the number of transgene copies generally correlated with the levels of expression of the transgenic CD3 proteins, we concluded that over-expression of the CD3 protein was the likely cause of the block in T lymphocyte development. The T cell immunodeficiency was caused by either the human or the murine CD3 protein. Since transgene coded mRNAs were found in significantly higher quantities than endogenous CD3 mRNAs in fetal thymi on days 13 and 14 of gestation, over-expression took place very early in development, probably prematurely. Over-expression of the CD3 transgene in thymocyte precursors may therefore affect T lymphocyte development in the absence of TCR and possibly in the absence of the other CD3 proteins. More importantly, over-expression of the CD3 protein in thymocytes of mice with a low copy number of transgenes had a significant effect on late thymic development Over-expression of the CD3 protein in immature thymocytes mimicked the effects caused by exposure of CD4–; CD8– thymocytes to anti-CD3 treatment: apoptosis and lack of TCRß expression. We therefore speculate that in the homozygous tg26 animals the arrest in T cell development was caused by excessive signal transduction events rather than by a toxic effect of the transgenic protein.
Keywords: apoptosis, over-expression of CD3, transgenic mice
Received 16 September 1994, accepted 18 November 1994.
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