The CD3γ chain is essential for development of both the TCRαβ and TCRγδ lineages

CD3 gamma and CD3 delta are the most closely related CD3 components, both of which participate in the TCR alpha beta-CD3 complex expressed on mature T cells. Interestingly, however, CD3 delta does not appear to participate functionally in the pre-T-cell receptor (TCR) complex that is expressed on immature T cells: disruption of CD3 delta gene expression has no effect on the developmental steps controlled by the pre-TCR, Here we report that in contrast with CD3 delta, CD3 gamma is an essential component of the pre-TCR. We generated mice selectively lacking expression of CD3 gamma, in which expression of CD3 delta, CD3 epsilon, CD3 zeta, pT alpha and TCR beta remained undisturbed. Thus, all components for composing a pre-TCR are available, with the exception of CD3 gamma. Nevertheless, T-cell development is severely inhibited in CD3 gamma-deficient mice, The number of cells in the thymus is reduced to <1% of that in normal mice, and the large majority of thymocytes lack CD4 and CD8 and are arrested at the CD44(-)CD25(+) double negative (DN) stage of development. Peripheral lymphoid organs are also practically devoid of T cells, with absolute numbers of peripheral T cells reduced to only 2-5% of those in normal mice. Both TCR alpha beta and TCR gamma delta lineages fail to develop effectively in CD3 gamma-deficient mice, although absence of CD3 gamma has no effect on gene rearrangements of the TCR beta, delta and gamma loci. Furthermore, absence of CD3 gamma results in a severe reduction in the level of TCR and CD3 epsilon expression at the cell surface of thymocytes and peripheral T cells. The defect in the DN to double positive transition in mice lacking CD3 gamma can be overcome by anti-CD3 epsilon-mediated cross-linking. CD3 gamma is thus essential for pre-TCR function.