T^-B⁺NK⁺ severe combined immunodeficiency caused by complete deficiency of the CD3ζ subunit of the T-cell antigen receptor complex

CD3ζ 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 TCRmediated signal transduction.We report here a patient with T ^-B⁺NK⁺ severe combined immunodeficiency (SCID)whowashomozygous for a single C insertion following nucleotide 411 in exon 7 of the CD3ζ gene. The few T cells present contained no detectable CD3ζ protein, expressed low levels of cell surface CD3ζ, and were nonfunctional. CD4⁺CD8^-CD3ε^low, CD4 ^-CD8⁺CD3ε^low, and CD4^-CD8 ^-CD3ε^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 CD3ζ cDNA failed to rescue assembly of nascent complete TCR complexes or surface TCR expression in CD3ζ-deficient MA5.8 murine T-cell hybridoma cells. Nascent transduced mutant CD3ζ 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 CD3ζ deficiency in humans can cause SCID by preventing normal TCR assembly and surface expression.