Over-expression of CD3 epsilon transgenes blocks T lymphocyte development

Area of Science:

• Immunology
• Molecular Biology
• Developmental Biology

Background:

• Mice with over 30 copies of the human CD3 epsilon transgene exhibit a complete loss of T lymphocytes and NK cells.
• Previous studies indicated a severe immunodeficiency in these transgenic mice.

Purpose of the Study:

• To investigate the cause of T lymphocyte and NK cell loss in mice with high copy numbers of the CD3 epsilon transgene.
• To determine the developmental stage and mechanism of T cell development arrest.

Main Methods:

• Immunohistology to examine thymus structure and cell populations.
• Cell surface phenotyping and TCR alpha/beta rearrangement studies.
• Analysis of multiple transgenic mouse lines with varying transgene copy numbers and constructs.

Main Results:

• The most immunodeficient mouse model (tg epsilon 26) displayed a severely hypoplastic thymus lacking mature T lymphocytes.
• T cell development arrest occurred earlier than in rag-1/2 or TCR beta null mice.
• Severity of T cell deficiency correlated with transgene copy number and CD3 epsilon expression levels.
• Over-expression of CD3 epsilon, even without TCR, affected early thymocyte development.
• Late thymic development was impacted by CD3 epsilon over-expression, causing apoptosis and inhibiting TCR beta expression.

Conclusions:

• Over-expression of the CD3 epsilon protein is the likely cause of T lymphocyte development arrest.
• Early and premature over-expression of CD3 epsilon in thymocyte precursors disrupts T cell development.
• Excessive signal transduction, rather than a toxic effect, is the probable mechanism behind the T cell immunodeficiency.