CD3 epsilon and CD3 zeta cytoplasmic domains can independently generate signals for T cell development and function.

To determine whether CD3 epsilon and CD3 zeta proteins have unique roles in TCR-dependent functions, chimeric genes encoding the extracellular and transmembrane domains of the human IL-2 receptor alpha chain (Tac) fused to a cytoplasmic domain of either the CD3 epsilon or CD3 zeta chain were introduced as transgenes into both normal and RAG2-deficient (RAG2-/-) mice. Developmental arrest of T lineage cells at the CD4, CD8 double-negative stage in the transgenic RAG2-/- thymus was released to the CD4, CD8 double-positive (DP) stage by in vivo cross-linking of TT epsilon or TT zeta with anti-Tac antibody. In TT epsilon + or TT zeta +, RAG2-/- mice, in vitro cross-linking of TT epsilon and TT zeta induced DP thymocyte cell death and proliferation of mature single-positive T cells. Overall, no qualitative differences were observed between TT epsilon- and TT zeta-mediated functions, suggesting that different CD3 components deliver qualitatively similar signals in inducing TCR-dependent functions.