Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.99.7 (sialyltransferase)
 1,534 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TCR reactivity is tuned during thymic development. Immature thymocytes respond to low-affinity self-ligands resulting in positive selection. Following differentiation, T cells no longer respond to low-affinity ligands, but respond well to high-affinity (foreign) ligands. We show in this study that this response includes integrin activation, supramolecular activation cluster formation, Ca(2+) flux, and CD69 expression. Because glycosylation patterns are known to change during T cell development, we tested whether alterations in sialylation influence CD8 T cell sensitivity to low affinity TCR ligands. Using neuraminidase treatment or genetic deficiency in the ST3Gal-I sialyltransferase, we show that desialylation of mature CD8 T cells enhances their sensitivity to low-affinity ligands, although these treatments do not completely recapitulate the dynamic range of immature T cells. These studies identify sialylation as one of the factors that regulate CD8 T cell tuning during development.
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PMID:Thymocyte sensitivity and supramolecular activation cluster formation are developmentally regulated: a partial role for sialylation. 1456 24

The CD8 coreceptor plays a crucial role in thymocyte and T cell sensitivity by binding to class I MHC and recruiting downstream signaling molecules to the TCR. Previous studies reported considerable changes in TCR-independent CD8/class I MHC binding (i.e., CD8 noncognate interactions) during T cell development, changes that correlated with altered glycosylation of surface molecules. In particular, expression of the sialyltransferase ST3Gal-I has been proposed as a critical factor regulating the attenuation of CD8 avidity during the double-positive to CD8 single-positive progression. This hypothesis is strengthened by the fact that ST3Gal-I(-/-) animals show a profound disregulation of CD8 T cell homeostasis. In contrast to this model, however, we report in this study that ST3Gal-I deficiency had no detectable impact on CD8 noncognate binding to multimeric peptide/MHC class I ligands at any stage of thymocyte development. We also found that the susceptibility to CD8-induced cell death is not markedly influenced by ST3Gal-I deficiency. Thus, the profound effects of ST3Gal-I on CD8 T cell survival evidently do not involve a role for this enzyme in controlling CD8-class I binding.
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PMID:The sialyltransferase ST3Gal-I is not required for regulation of CD8-class I MHC binding during T cell development. 1675 87

During T-cell development and activation, dramatic changes occur in glycan structures that decorate cell-surface glycoproteins. These changes have been considered to be general cellular events that affect many glycans on many glycoproteins. For example, loss of sialic acid from core 1 O-glycans on T-cell surface glycoproteins CD45, CD43 and CD8, detected with peanut agglutinin (PNA), is a hallmark of immature thymocytes and activated peripheral T cells. Loss of cell-surface sialic acid during T-cell activation has been proposed to enhance TCR reactivity with antigen. However, CD4 T-cell activation also results in increased binding of the CZ-1 antibody that recognizes a sialic acid-containing epitope on CD45RB. This indicates that increased sialylation of the CZ-1 epitope occurs during CD4 T cell activation, and that loss of cell surface sialic acid during T-cell activation is a selective event rather than affecting all cell surface glycans. As specific glycans on specific glycoprotein backbones control critical events in T-cell maturation and survival, understanding mechanisms of selective glycoprotein glycosylation is important for regulating T-cell development and function. We define the sialylated O-glycan epitope recognized by CZ-1, and find that, paradoxically, CZ-1 and PNA binding are simultaneously increased on activated CD4(+) T cells, demonstrating site-specific changes in CD45 sialylation. Moreover, we identify ST3Gal I as the sialyltransferase responsible for creating the CZ-1 epitope. Thus, changes in glycan structure during T-cell activation are microheterogeneous and unique to individual glycans on specific glycoproteins, implying that these glycans have precise functions in T-cell biology.
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PMID:T-cell activation results in microheterogeneous changes in glycosylation of CD45. 1760 81