Specific requirement for CD3ε in T cell development

T cell antigen receptor (TCR) and pre-TCR complexes are composed of clonotypic heterodimers in association with dimers of signal transducing invariant subunits (CD3 gamma, -delta, -epsilon, and zeta). The role of individual invariant subunits in T cell development has been investigated by generating gene-specific mutations in mice. Mutation of CD3 gamma, -delta, or zeta results in an incomplete block in development, characterized by reduced numbers of mature T cells that express low levels of TCR. In contrast, mature T cells are absent from CD3 epsilon(-/-) mice, and thymocyte development is arrested at the early CD4(-)CD8(-) stage, Although these results suggest that CD3 epsilon is essential for pre-TCR and TCR expression/function, their interpretation is complicated by the fact that expression of the CD3 gamma and CD3 delta genes also is reduced in CD3 epsilon(-/-) mice. Thus, it is unclear whether the phenotype of CD3 epsilon(-/-) mice reflects the collective effects of CD3 gamma, -delta, and -epsilon deficiency. By removing the selectable marker (PGH-NEO) from the targeted CD3 epsilon gene via Cre/loxP-mediated recombination, we generated mice that lack CD3 epsilon yet retain normal expression of the closely linked CD3 gamma and CD3 delta genes. These (CD3 epsilon(Delta/Delta)) mice exhibited an early arrest in T cell development, similar to that of CD3 epsilon(-/-) mice. Moreover, the developmental defect could be rescued by expression of a CD3 epsilon transgene. These results identify an essential role for CD3E in T cell development not shared by the CD3 gamma, CD3 delta, or zeta-family proteins and provide further evidence that PGK-NEO can influence the expression of genes in its proximity.