Altered proximal T cell receptor (TCR) signaling in human CD4+CD25+ regulatory T cells

Julia Yuen-Shan Tsang, Niels Olsen Saraiva Camara, Efrem Eren, Helga Schneider, Christopher Rudd, Giovanna Lombardi, Robert Lechler

    Research output: Contribution to journalArticlepeer-review

    36 Citations (Scopus)

    Abstract

    CD4+CD25+ regulatory T cells play an important role in peripheral tolerance. Upon T cell receptor (TCR)-mediated activation, the cells fail to proliferate but are induced to have a suppressor function. The intracellular signaling events that lead to their responses have not been elucidated. In this study, we have examined the proximal TCR signaling events in freshly isolated human CD4+CD25+ regulatory T cells after TCR ligation. In contrast to CD4+CD25- T cells, TCR ligation of CD4+CD25+ regulatory T cells by anti-CD3 cross-linking resulted in a lower calcium influx and extracellular signal-regulated kinase 1/2 phosphorylation. Examination of the CD3zeta chain phosphorylation status indicated that CD4+CD25+ regulatory T cells have poor phosphorylation of the protein and consequently, reduced recruitment of zeta-associated protein-70 to the TCR immunoreceptor tyrosine motif. The adaptor protein, Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa, which relays signals to downstream signaling components, also showed reduced phosphorylation, which correlated with reduced VAV guanine nucleotide exchange factors association. Consistent with other findings, the defect is accompanied with impaired actin cap formation, implicating a failure of actin remodeling of the cells. Together, our results demonstrate that CD4+CD25+ regulatory T cells have altered TCR proximal signaling pathways, which could be critical for inducing the distinct behavior of these cells.
    Original languageEnglish
    Pages (from-to)145-151
    Number of pages7
    JournalJournal of Leukocyte Biology
    Volume80
    Issue number1
    Early online date9 May 2006
    DOIs
    Publication statusPublished - Jul 2006

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