['Specific T-cell activation requires T-cell receptor stimulation and the generation of costimulatory signals. Major costimulatory signals are delivered to T cells by the interaction of CD28 and inducible costimulator (ICOS).', 'To investigate the molecular pathways involved in direct T-cell suppression by IL-10.', 'T-cell proliferation analysis, immunoprecipitations, and Western blots were performed after T-cell receptor and CD28 and ICOS stimulations in the absence or presence of IL-10. Dominant-negative src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) overexpression, small inhibitory RNA, and SHP-1-deficient and IL-10-deficient mice were used.', 'IL-10 receptor-associated tyrosine kinase Tyk-2 acts as a constitutive reservoir for SHP-1 in resting T cells, and then tyrosine phosphorylates SHP-1 on IL-10 binding. SHP-1 rapidly binds to CD28 and ICOS costimulatory receptors and dephosphorylates them within minutes. In consequence, the binding of phosphatidylinositol 3-kinase to either costimulatory receptor no longer occurs, and downstream signaling is inhibited. Accordingly, spleen cells from SHP-1-deficient mice showed increased proliferation with CD28 and ICOS stimulation in comparison with wild-type mice, which was not suppressed by IL-10. Generation of dominant-negative SHP-1-overexpressing T cells or silencing of the SHP-1 gene by small inhibitory RNA both altered SHP-1 functions and abolished the T-cell suppressive effect of IL-10.'] Does iL-10 inhibit CD28 and ICOS costimulations of T cells via src homology 2 domain-containing protein tyrosine phosphatase 1?