title: Development of autologous, oligoclonal, poorly functioning T lymphocytes in a patient with autosomal recessive severe combined immunodeficiency caused by defects of the Jak3 tyrosine kinase.
abstract: Defects of the common gamma chain subunit of the cytokine receptors (gamma c) or of Jak3, a tyrosine kinase required for gamma c signal transduction, result in T-B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (> 3,000/microL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+ HLA-DR+ CD62L(lo)), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in gamma c-/y and in Jak3-/- mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.
authors.affiliation: Servizio di Immunologia Clinica, III Laboratorio Analisi, Spedali Civili, Brescia, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Brugnoni
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: A
authors.initials: A
authors.lastname: Sottini
authors.forename: P
authors.initials: P
authors.lastname: Airò
authors.forename: M
authors.initials: M
authors.lastname: Pennacchio
authors.forename: E
authors.initials: E
authors.lastname: Mazzolari
authors.forename: S
authors.initials: S
authors.lastname: Signorini
authors.forename: F
authors.initials: F
authors.lastname: Candotti
authors.forename: A
authors.initials: A
authors.lastname: Villa
authors.forename: P
authors.initials: P
authors.lastname: Mella
authors.forename: P
authors.initials: P
authors.lastname: Vezzoni
authors.forename: R
authors.initials: R
authors.lastname: Cattaneo
authors.forename: A G
authors.initials: AG
authors.lastname: Ugazio
authors.forename: L
authors.initials: L
authors.lastname: Imberti
mesh_terms: D016923:Cell Death; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D007231:Infant, Newborn; D053616:Janus Kinase 3; D008213:Lymphocyte Activation; D008297:Male; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology
chemical_list: D016207:Cytokines; D019253:Proto-Oncogene Proteins c-bcl-2; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3