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.