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 Blood, 15 April 2007, Vol. 109, No. 8, pp. 3198-3206.
Prepublished online as a Blood First Edition Paper on December 14, 2006; DOI 10.1182/blood-2006-08-043166.

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Submitted August 25, 2006
Accepted December 5, 2006

T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3{zeta} subunit of the T cell antigen receptor complex

Joseph L. Roberts*, Jens Peter H. Lauritsen, Myriah Cooney, Roberta E. Parrott, Elisa O. Sajaroff, Chan M. Win, Michael D. Keller, Jeffery H. Carpenter, Juan Carabana, Michael S. Krangel, Marcella Sarzotti, Xiao-Ping Zhong, David L. Wiest, and Rebecca H. Buckley

Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
Division of Basic Sciences, Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, PA, United States
Department of Immunology, Duke University Medical Center, Durham, NC, United States

* Corresponding author; email: rober060{at}mc.duke.edu.

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 non-functional. 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.


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