T-B+NK+ Severe Combined Immunodeficiency Caused by Complete Deficiency of the CD3zeta Subunit of the T Cell Antigen Receptor Complex

CD3 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 TCRmediatedsignaltransduction.Wereporthere a patient with TBNK severe combined immunodeficiency(SCID)whowashomozygousforasingleCinsertionfollowingnucleotide 411 in exon 7 of the CD3 gene. The few T cells present contained no detectable CD3 protein, expressed low levels of cell surface CD3, and were nonfunctional. CD4CD8CD3low, CD4CD8CD3low, and CD4CD8CD3low cells were detected in the periphery, and the patient also exhibited an unusual population of CD56CD16 NK cells with diminished cytolytic activity. Additional studies demonstrated that retrovirally transduced patient mutant CD3 cDNA failed to rescue assembly of nascent complete TCR complexes or surface TCR expression in CD3deficient MA5.8 murine T-cell hybridoma cells. Nascent transduced mutant CD3 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 deficiency in humans can cause SCID by preventing normal TCR assembly and surface expression. (Blood. 2007; 109:3198-3206)