T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex.
CD3zeta 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 CD3zeta gene. The few T cells present contained no detectable CD3zeta protein, expressed low levels of cell surface CD3epsilon, and were nonfunctional. CD4(+)CD8(-)CD3epsilon(low), CD4(-)CD8(+)CD3epsilon(low), and CD4(-)CD8(-)CD3epsilon(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 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, suggesting that it was unstable and rapidly degraded. Taken together, these findings provide the first demonstration that complete CD3zeta deficiency in humans can cause SCID by preventing normal TCR assembly and surface expression.
Roberts
Joseph L
JL
Department of Pediatrics and Immunology, Duke University Medical Center, Durham, NC 27710, USA. rober060@mc.duke.edu
Lauritsen
Jens Peter H
JP
Cooney
Myriah
M
Parrott
Roberta E
RE
Sajaroff
Elisa O
EO
Win
Chan M
CM
Keller
Michael D
MD
Carpenter
Jeffery H
JH
Carabana
Juan
J
Krangel
Michael S
MS
Sarzotti
Marcella
M
Zhong
Xiao-Ping
XP
Wiest
David L
DL
Buckley
Rebecca H
RH
D001402:B-Lymphocytes / Q000276:immunology*; D017252:CD3 Complex / Q000235:genetics* / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002460:Cell Line; D005091:Exons / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology*; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology; D016254:Mutagenesis, Insertional; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D012190:Retroviridae; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D015704:CD4 Antigens; D016827:CD8 Antigens; D046912:Multiprotein Complexes; D011948:Receptors, Antigen, T-Cell