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Published online before print May 9, 2006

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(Journal of Leukocyte Biology. 2006;80:145-151.)
© 2006 by Society for Leukocyte Biology

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^* and Robert Lechler^*,1

^* Nephrology and Transplantation, Guy’s King’s St Thomas’ Medical School, Guy’s Hospital, London, United Kingdom;
Department of Immunology, University of São Paulo, Cidade University, Brazil; and
Immunology and
Molecular Immunology Section, Hammersmith Campus, Imperial College London, United Kingdom

¹ Correspondence: Immunoregulation Laboratory, Nephrology and Transplantation, Guy’s King’s St Thomas’ Medical School, Guy’s Hospital, London, SE1 9RT, UK. E-mail: robert.lechler{at}kcl.ac.uk

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 CD3 chain phosphorylation status indicated that CD4+CD25+ regulatory T cells have poor phosphorylation of the protein and consequently, reduced recruitment of -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.

Key Words: T cell activation • signal transduction • immunoregulation

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