text: CD4+ T cells orchestrate the Th1-type cell-mediated immune response in RA [22]. Activated CD4+ T cells stimulate macrophages, synovial fibroblasts, B cells, and osteoclasts through the expression of cell surface molecules and Th1 cytokines, thereby contributing to both the chronic inflammation and the joint destruction. CD4+ T cells require two signals to be activated; antigen receptor occupancy and CD28-mediated costimulation. In the ST lesion, the CD28 ligands, both CD80 and CD86, together with MHC class II antigens, are substantially expressed by antigen-presenting cells such as macrophages and dendritic cells [18-20]. The significance of CD28 engagement in the T-cell-mediated disease process has recently been proven by the clinical efficacy of its blocker cytotoxic T-cell-associated antigen 4 (CD152)-IgG in RA patients [23]. 
  IL-10 plays a predominant role in limiting immune and inflammatory responses by regulating the function of both macrophages and Th1 cells [1]. IL-10 inhibits the tyrosine phosphorylation of the CD28 molecule and the subsequent phosphatidylinositol 3-kinase binding in T cells, and thereby directly acts on T cells [24]. In the present study, we found that PB CD4+ T cells from patients with active RA, in the presence of IL-10, are able to produce higher levels of IFN-gamma after CD3 and CD28 costimulation than normal CD4+ T cells. Despite high-level IL-10R1 expression and constitutive STAT3 activation, IL-10-induced tyrosine phosphorylation of STAT3 is suppressed in RA CD4+ T cells, in contrast to normal CD4+ T cells, where STAT3 phosphorylation is dose-dependently inducible by IL-10. Serum IL-6 from RA patients induces STAT3 but not STAT1 phosphorylation in normal CD4+ T cells, and exogenous IL-6 induces the resistance to IL-10 inhibition of IFN-gamma production. RA CD4+ T cells contain higher levels of SOCS1 but contain lower levels of SOCS3 transcripts in comparison with normal CD4+ T cells. These findings indicate that CD4+ T cells become resistant to the inhibitory effect of IL-10 before migration into the inflamed ST, and suggest that this resistance may be attributable to impaired IL-10-dependent STAT3 activation, in association with sustained STAT3 phosphorylation and SOCS1 induction. 
  IL-10-mediated inhibition of CD4+ T-cell cytokine production is principally dependent on its inhibition of macrophage antigen-presenting cell function [1]. However, this indirect inhibitory effect is thought to be restricted at the site of T-cell activation in RA, because macrophages in the ST express high levels of cytokines, CD80 and CD86 molecules, and MHC class II antigens [10,18-20]. More recently, IL-10 has been shown to induce the antigen-specific T-cell unresponsiveness by inhibiting CD28 tyrosine phosphorylation [33]. This direct effect also may be limited in active RA patients, because their PB CD4+ T cells showed a defective IL-10 inhibition of CD28-costimulated production of both IFN-gamma and IL-2. 
  