TY - JOUR
T1 - T cell activation deficiency associated with an aberrant pattern of protein tyrosine phosphorylation after CD3 perturbation in Down's syndrome
AU - Scotese, Immacolata
AU - Gaetaniello, Lucia
AU - Matarese, Giuseppe
AU - Lecora, Margherita
AU - Racioppi, Luigi
AU - Pignata, Claudio
PY - 1998/8
Y1 - 1998/8
N2 - Children affected by Down's syndrome (DS) have an increased susceptibility to viral or bacterial infections and leukemia, associated with several abnormalities of the immune system. We investigated whether the T cell defect was qualitative in nature and associated with abnormalities of the early events occurring during cell activation. The proliferative response of lymphocytes from DS individuals after CD3 cross-linking was clearly depressed, as already reported. In contrast, phorbol ester and ionomycin were able to induce cell cycle progression in DS, suggesting a defect in the early stages of the signal transduction through a T cell receptor/CD3 (TCR/CD3) complex upstream of protein kinase C activation. The functional impairment in DS was not related either to a decrease of circulating mature-type CD3+ cells, which express high levels of surface of CD3 molecules, or to a decrease of the CD4+ subpopulation. The analysis of phosphotyrosine- containing proteins after the cross-linking of CD3 molecules in DS lymphocytes revealed a partial signaling, characterized by increased phosphorylation of proteins of 42-44 kD, comparable to that observed in control subjects, but not of proteins of 70 and 21 kD. Moreover, although the 'anti-anergic' γ element of IL-2, IL-4, IL-7, and IL-15 receptors was normally tyrosine-phosphorylated during cell activation, the CD3 ζ- associated protein kinase (ZAP-70) was not. Our results indicate that in DS there is a T cell activation defect, characterized by partial signal transduction through a TCR/CD3 complex, and associated with a selective failure of ZAP-70 tyrosine phosphorylation.
AB - Children affected by Down's syndrome (DS) have an increased susceptibility to viral or bacterial infections and leukemia, associated with several abnormalities of the immune system. We investigated whether the T cell defect was qualitative in nature and associated with abnormalities of the early events occurring during cell activation. The proliferative response of lymphocytes from DS individuals after CD3 cross-linking was clearly depressed, as already reported. In contrast, phorbol ester and ionomycin were able to induce cell cycle progression in DS, suggesting a defect in the early stages of the signal transduction through a T cell receptor/CD3 (TCR/CD3) complex upstream of protein kinase C activation. The functional impairment in DS was not related either to a decrease of circulating mature-type CD3+ cells, which express high levels of surface of CD3 molecules, or to a decrease of the CD4+ subpopulation. The analysis of phosphotyrosine- containing proteins after the cross-linking of CD3 molecules in DS lymphocytes revealed a partial signaling, characterized by increased phosphorylation of proteins of 42-44 kD, comparable to that observed in control subjects, but not of proteins of 70 and 21 kD. Moreover, although the 'anti-anergic' γ element of IL-2, IL-4, IL-7, and IL-15 receptors was normally tyrosine-phosphorylated during cell activation, the CD3 ζ- associated protein kinase (ZAP-70) was not. Our results indicate that in DS there is a T cell activation defect, characterized by partial signal transduction through a TCR/CD3 complex, and associated with a selective failure of ZAP-70 tyrosine phosphorylation.
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M3 - Article
C2 - 9702923
AN - SCOPUS:0031854015
VL - 44
SP - 252
EP - 258
JO - Pediatric Research
JF - Pediatric Research
SN - 0031-3998
IS - 2
ER -