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

Abstract

RATIONALE: CD3ζɛτα 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. Hence, we hypothesized complete CD3ζɛτα deficiency would result in severe combined immunodeficiency (SCID). METHODS: TCR complex expression was analyzed in purified CD3ɛπσιλoνlow cells from a patient with T-B+NK+ SCID. Patient lymphocyte subsets were analyzed by flow cytometry. CD3ζɛτα gene mutation analysis was performed by automated DNA sequencing. Additional studies included analysis of TCR expression in retrovirally-transduced CD3ζɛτα-deficient MA5.8 cells. RESULTS: The patient was homozygous for a deleterious mutation in the CD3ζɛτα gene. The few T cells present contained no detectable CD3ζɛτα protein or complete TCR complexes, and only expressed low levels of incomplete TCR complexes on the cell surface that contained CD3ɛπσιλoν in the absence of TCRαλπηαβɛτα or TCRgammadelta and were non-functional. The patient also expressed large numbers of CD3epsilonlow CD4-CD8- cells in the periphery, and exhibited an unusual population of CD56-CD16+ NK cells with diminished cytolytic activity. Retrovirally-transduced patient mutant CD3zeta cDNA failed to rescue assembly of nascent complete TCR complexes or surface TCR expression in CD3zeta-deficient MA5.8 murine T cell hybridoma cells. Nascent transduced mutant CD3zeta protein was also not detected in metabolically labeled MA5.8 cells, demonstrating that it was unstable and rapidly degraded. CONCLUSION: Taken together, these findings provide the first demonstration that complete CD3ζɛτα deficiency in humans can cause SCID by preventing assembly and surface expression of complete TCR complexes.