T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3ξ subunit of the T-cell antigen receptor complex

CD3 zeta is a subunit of the T-cell antigen receptor (TCR) complex required for its assembly and surface expression that also plays an important role in TCR-mediated signal transduction. We report here a patient with T-B+NK+ severe combined immunodeficiency (SCID) who was homozygous for a single C insertion following nucleotide 411 in exon 7 of the CD3 zeta gene. The few T cells present contained no detectable CD3 zeta protein, expressed low levels of cell surface CD3 epsilon, and were nonfunctional. CD4(+)CD8(-)CD3 epsilon(low), CD4(-)CD8(+)CD3 epsilon(low), and CD4(-)CD8(-)CD3 epsilon(low) cells were detected in the periphery, and the patient also exhibited an unusual population of CD56(-)CD16(+) NK cells with diminished cytolytic activity. Additional studies demonstrated that retrovirally transduced patient mutant CD3 zeta cDNA failed to rescue assembly of nascent complete TCR complexes or surface TCR expression in CD3 zeta-deficient MA5.8 murine T-cell hybridoma cells. Nascent transduced mutant CD3 zeta protein was also not detected in metabolically labeled MA5.8 cells, suggesting that it was unstable and rapidly degraded. Taken together, these findings provide the first demonstration that complete CD3 zeta deficiency in humans can cause SCID by preventing normal TCR assembly and surface expression.