PD-L1 negatively regulates CD4+CD25+Foxp3+ tregs by limiting STAT-5 phosphrylation in patients chronically infected with HCV

CD4+CD25+Foxp3+ Tregs suppress autoimmune responses. In addition, they limit T cell responses during
chronic infection, thereby minimizing T cell–dependent immunopathology. We sought to investigate how
Tregs are regulated in the livers of patients chronically infected with HCV, where they control the balance
between an adequate protective immune response and suppression of immunopathology. We found that,
despite accumulating and proliferating at sites of infection in the livers of patients chronically infected with
HCV, Tregs were relatively less expanded than CD4+CD25+Foxp3– effector T cells. The relative lower expansion
of intrahepatic Tregs coincided with their upregulation of programmed death–1 (PD-1). PD-1 expression
inversely correlated with both Treg proliferation and clinical markers of immune suppression in vivo. Consistent
with the possibility that PD-1 controls Tregs, blockade of the interaction between PD-1 and programmed
death–1 ligand 1 (PD-L1) enhanced the in vitro expansion and function of Tregs isolated from the livers of
patients chronically infected with HCV. Blockade of the interaction between PD-L1 and B7.1 also improved
the proliferation of these cells. Interestingly, both PD-1 and phosphorylated STAT-5 were overexpressed in
intrahepatic Tregs in a parallel fashion in steady disease conditions, and in an alternate-fluctuating fashion
during the course of severe hepatitis reactivation. Notably, PD-L1 blockade upregulated STAT-5 phosphorylation
in Tregs ex vivo. These data suggest that PD-L1 negatively regulates Tregs at sites of chronic inflammation
by controlling STAT-5 phosphorylation.