No abstract

No abstract

The T cell antigen receptor (TCR)‐associated invariable membrane proteins (CD3‐gamma, ‐delta, ‐epsilon and ‐zeta) are critical to the assembly and cell surface expression of the TCR/CD3 complex and to signal transduction upon engagement of TCR with antigen. Disruption of the CD3‐zeta gene by homologous recombination resulted in a structurally abnormal thymus which primarily contained CD4‐ CD8‐ and TCR/CD3very lowCD4+CD8+ cells. Spleen and lymph nodes of CD3‐zeta‐/‐ mutant mice contained a normal number and ratio of CD4+ and CD8+ single positive cells that were TCR/CD3very low. These splenocytes did not respond to antibody cross‐linking or mitogenic triggering. The V beta genes of CD4‐CD8‐ and CD4+CD8+ thymocytes and splenic T cells were productively rearranged. These data demonstrated that (i) in the absence of the CD3‐zeta chain, the CD4‐ CD8‐ thymocytes could differentiate to CD4+CD8+ TCR/CD3very low thymocytes, (ii) that thymic selection might have occurred, (iii) but that the transition to CD4+CD8‐ and CD4‐CD8+ cells took place at a very low rate. Most strikingly, intraepithelial lymphocytes (IELs) isolated from the small intestine or the colon expressed normal levels of TCR/CD3 complexes on their surface which contained Fc epsilon RI gamma homodimers. In contrast to CD3‐zeta containing IELs, these cells failed to proliferate after triggering with antibody cross‐linking or mitogen. In comparison to thymus‐derived peripheral T cells in the spleen and lymph nodes, the preferential expression of normal levels of TCR/CD3 in intestinal IELs suggested they mature via an independent extrathymic pathway.

The quantitative data that we have obtained fulfill the predictions of the stochastic hypothesis: that is, a progenitor T cell first attempts to become a gamma delta T cell and, if unsuccessful, then attempts to become an alpha beta T cell. Thus, alpha beta and gamma delta T cells can derive from a common precursor thymocyte. In the simplest case, therefore, lineage-determining factors are the successful rearrangement of both gamma and delta genes before TCR alpha gene rearrangements occur, which lead to deletion of the TCR delta locus and thereby preclude further gamma delta T-cell differentiation. In contrast, successful rearrangement of the TCR beta locus remains compatible with cells becoming either gamma delta or alpha beta T cells.