title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.
abstract: We investigated the molecular mechanism underlying a severe combined immunodeficiency characterized by the selective and complete absence of T cells. The condition was found in 5 patients and 2 fetuses from 3 consanguineous families. Linkage analysis performed on the 3 families revealed that the patients were carrying homozygous haplotypes within the 11q23 region, in which the genes encoding the gamma, delta, and epsilon subunits of CD3 are located. Patients and affected fetuses from 2 families were homozygous for a mutation in the CD3D gene, and patients from the third family were homozygous for a mutation in the CD3E gene. The thymus from a CD3delta-deficient fetus was analyzed and revealed that T cell differentiation was blocked at entry into the double positive (CD4+CD8+) stage with the accumulation of intermediate CD4-single positive cells. This indicates that CD3delta plays an essential role in promoting progression of early thymocytes toward double-positive stage. Altogether, these findings extend the known molecular mechanisms underlying severe combined immunodeficiency to a new deficiency, i.e., CD3epsilon deficiency, and emphasize the essential roles played by the CD3epsilon and CD3delta subunits in human thymocyte development, since these subunits associate with both the pre-TCR and the TCR.
authors.affiliation: Unité Développement Normal et Pathologique du Système Immunitaire, INSERM U 429, Paris, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
authors.forename: Frédéric
authors.initials: F
authors.lastname: Geissmann
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Flori
authors.forename: Béatrice
authors.initials: B
authors.lastname: Uring-Lambert
authors.forename: Claire
authors.initials: C
authors.lastname: Soudais
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
mesh_terms: D017252:CD3 Complex / Q000235:genetics*; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002880:Chromosomes, Human, Pair 11; D003241:Consanguinity; D005260:Female; D016368:Frameshift Mutation; D008040:Genetic Linkage; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000209:etiology* / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D017260:Receptor-CD3 Complex, Antigen, T-Cell