CTLA-4 is not constitutively expressed on effector T cells but is rapidly induced upon TCR engagement.14 In patients with CHB, we found a greater propensity for the induction of CTLA-4 upon TCR stimulation with either mitogen or cognate peptide, with CTLA-4 induction in HBV-specific CD8 T cells correlating strongly with viral load. These data are in line with recent demonstrations that CTLA-4 plays a critical role in the effector T-cell compartment in addition to its contribution to regulatory T-cell function.15, 16 CTLA-4 mediated inhibition may depend
on the fact that it shares ligands (B7-1 and B7-2) with CD28 but has higher avidity; when the supply STI571 order of these ligands is limited, CTLA-4-mediated inhibitory signaling could override CD28-mediated positive costimulation.
In CHB, the ability of CTLA-4 to outcompete CD28 may be favored not only by the increase in CTLA-4, but also by the reduced levels of CD28 on CD8 T cells17 and by the scarcity of B7 selleck monoclonal antibody ligands on hepatocytes and other intrahepatic cells with antigen-presenting capability.18 We postulated that CTLA-4-mediated coinhibition may be one of the pathways that drives T cells encountering their antigen in the liver towards Bim-dependent apoptosis. In support of this, we found the highest intracellular levels of Bim in CTLA-4hi HBV-specific CD8 T cells. We speculate that CTLA-4 signaling may induce Bim by its capacity to reduce availability of IL-214 while increasing
cell-intrinsic transforming growth factor beta (TGF-β),19 which is up-regulated at the transcriptional level in HBV-specific CD8 T cells2 and can promote Bim-dependent attrition of LCMV-specific T cells.20 In most patients with CHB without evidence of liver inflammation, blocking the CTLA-4 receptor was able to reduce Bim expression. However, in patients with CHB-related liver inflammation the lack of reduction in Bim achieved by CTLA-4 blockade invoked a dominant role for other factors in driving this proapoptotic phenotype. We have recently described a signaling defect reducing cell-autonomous production of IL-2 in patients with CHB-related liver inflammation17 oxyclozanide that may limit the efficacy of CTLA-4 blockade in such patients. In addition, as discussed below, a number of different coinhibitory pathways may play nonredundant roles in T-cell exhaustion in CHB. To explore the therapeutic potential to reprogram the tolerogenic phenotype of HBV-specific CD8 T cells we examined the impact of antiviral therapy. A previous study of CD8 T-cell reconstitution on antiviral monotherapy had suggested that viral load reduction resulted in some increase in cytolytic responses against HLA-A2 restricted HBV epitopes,21 but that these were of limited lifespan.