RESUMEN
The aim of this study was to understand how Syk affects peripheral T cell function. T cells from Syk-/- chimeric mice and DR1 Sykfl/fl CD4cre conditional mice gave strong CD3-induced Th1, Th2, and Th17 cytokine responses. However, an altered peptide ligand (APL) of human CII (256-276) with two substitutions (F263N, E266D), also called A12, elicited only Th2 cytokine responses from Sykfl/fl T cells but not Sykfl/fl-CD4cre T cells. Western blots revealed a marked increase in the phosphorylation of Syk, JNK and p38 upon A12/DR1 activation in WT or Sykfl/fl T cells but not in Sykfl/flCD4-cre cells. We demonstrate that Syk is required for the APL- induction of suppressive cytokines. Chemical Syk inhibitors blocked activation of GATA-3 by peptide A12/DR1. In conclusion, this study provides novel insights into the role that Syk plays in directing T cell activity, and may shape therapeutic approaches for autoimmune diseases.
Asunto(s)
Activación de Linfocitos/inmunología , Transducción de Señal/inmunología , Quinasa Syk/inmunología , Linfocitos T/inmunología , Animales , Colágeno Tipo II/genética , Colágeno Tipo II/inmunología , Colágeno Tipo II/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/inmunología , Factor de Transcripción GATA3/metabolismo , Humanos , Activación de Linfocitos/efectos de los fármacos , Ratones Endogámicos DBA , Ratones Noqueados , Ratones Transgénicos , Péptidos/inmunología , Péptidos/metabolismo , Péptidos/farmacología , Fosforilación , Proteínas Tirosina Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Estilbenos/farmacología , Quinasa Syk/antagonistas & inhibidores , Quinasa Syk/genética , Linfocitos T/enzimología , Linfocitos T/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
BACKGROUND: Viral culture plaque morphology in human cell lines are markers for growth capability and cytopathic effect, and have been used to assess viral fitness and select preattenuation candidates for live viral vaccines. We classified respiratory syncytial virus (RSV) plaque morphology and analyzed the relationship between plaque morphology as compared to subgroup, viral load and clinical severity of infection in infants and children. METHODS: We obtained respiratory secretions from 149 RSV-infected children. Plaque morphology and viral load was assessed within the first culture passage in HEp-2 cells. Viral load was measured by polymerase chain reaction (PCR), as was RSV subgroup. Disease severity was determined by hospitalization, length of stay, intensive care requirement, and respiratory failure. RESULTS: Plaque morphology varied between individual subjects; however, similar results were observed among viruses collected from upper and lower respiratory tracts of the same subject. Significant differences in plaque morphology were observed between RSV subgroups. No correlations were found among plaque morphology and viral load. Plaque morphology did not correlate with disease severity. CONCLUSION: Plaque morphology measures parameters that are viral-specific and independent of the human host. Morphologies vary between patients and are related to RSV subgroup. In HEp-2 cells, RSV plaque morphology appears unrelated to disease severity in RSV-infected children.
