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

CD4CD25 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 sup- pressor function. The intracellular signaling events that lead to their responses have not been eluci- dated. In this study, we have examined the proxi- mal TCR signaling events in freshly isolated human CD4CD25 regulatory T cells after TCR liga- tion. In contrast to CD4CD25- T cells, TCR ligation of CD4CD25 regulatory T cells by anti-CD3 cross-linking resulted in a lower cal- cium influx and extracellular signal-regulated ki- nase 1/2 phosphorylation. Examination of the CD3 chain phosphorylation status indicated that CD4CD25 regulatory T cells have poor phos- phorylation of the protein and consequently, re- duced recruitment of -associated protein-70 to the TCR immunoreceptor tyrosine motif. The adaptor protein, Src homology 2 domain-con- taining leukocyte phosphoprotein of 76 kDa, which relays signals to downstream signaling components, also showed reduced phosphoryla- tion, which correlated with reduced VAV guanine nucleotide exchange factors association. Consis- tent with other findings, the defect is accompa- nied with impaired actin cap formation, implicat- ing a failure of actin remodeling of the cells. Together, our results demonstrate that CD4CD25 regulatory T cells have altered TCR proximal signaling pathways, which could be critical for inducing the distinct behavior of these cells. J. Leukoc. Biol. 80: 145-151; 2006.