PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8⁺ T cell immune response via the interaction with PD-L1 expressed on CD8⁺ T cells

Regulatory T (T_reg) cells act as terminators of T cell immuniy during acute phase of viral infection; however, their role and suppressive mechanism in chronic viral infection are not completely understood. In this study, we compared the phenotype and function of T_reg cells during acute or chronic infection with lymphocytic choriomeningitis virus. Chronic infection, unlike acute infection, led to a large expansion of T_reg cells and their upregulation of programmed death-1 (PD-1). T_reg cells from chronically infected mice (chronic T_reg cells) displayed greater suppressive capacity for inhibiting both CD8⁺ and CD4⁺ T cell proliferation and subsequent cytokine production than those from naive or acutely infected mice. A contact between T_reg and CD8⁺ T cells was necessary for the potent suppression of CD8⁺ T cell immune response. More importantly, the suppression required cell-specific expression and interaction of PD-1 on chronic T_reg cells and PD-1 ligand on CD8⁺ T cells. Our study defines PD-1 upregulated on T_reg cells and its interaction with PD-1 ligand on effector T cells as one cause for the potent T cell suppression and proposes the role of PD-1 on T_reg cells, in addition to that on exhausted T cells, during chronic viral infection.