Re-Evaluation of PD-1 Expression by T Cells as a Marker for Immune Exhaustion during SIV Infection

Jung Joo Hong,Francois Villinger,Praveen K Amancha,Kenneth Rogers,Aftab A Ansari,Paul G Thomas

doi:10.1371/journal.pone.0060186

Abstract

PD-1 expression is generally associated with exhaustion of T cells during chronic viral infections based on the finding that PD-1 expressing cells respond poorly to antigen activation and blockade of PD-1/PD-ligand interaction restores such antigen specific responses in vitro. We tested this hypothesis by examining PD-1 expression on virus-specific CD8 T cells and total T cells in vivo to determine whether PD-1 expression constitutes a reliable marker of immune exhaustion during SIV infection. The expression of PD-1 and Ki67 was monitored longitudinally on T cell subsets in peripheral blood, bone marrow, lymph node and rectal biopsy specimens from rhesus macaques prior to and post infection with pathogenic SIVmac239. During the course of infection, a progressive negative correlation was noted between PD-1 density and Ki67 expression in p11CM+ CD8+ T cells, as seen in other studies. However, for total and memory CD4 and CD8 T cells, a positive correlation was observed between PD-1 and Ki67 expression. Thus, while the levels of non-proliferating PD-1+ p11CM+ CD8 T cells were markedly elevated with progressing infection, such an increase was not seen on total T cells. In addition, total memory PD1+ T cells exhibited higher levels of CCR5 than PD-1− T cells. Interestingly, few PD-1+ CD8+ T cells expressed CCR7 compared to PD-1+ CD4 T cells and PD-1− T cells. In conclusion, overall PD1+ T cells likely represent a particular differentiation stage or trafficking ability rather than exhaustion and in the context of chronic SIV infection, the level of PD-1 expression by T cells does not by itself serve as a reliable marker for immune exhaustion.

Highlights

Programmed cell death 1 (PD-1) is a member of the CD28 family, which modulates T cell function [1] and is primarily upregulated on the surface of CD4 and CD8 T cells upon activation [2]
During chronic viral antigenic stimulation, PD-1 can be highly upregulated, which when cross-linked by its cognate ligands, leads to T cell exhaustion characterized by loss of the proliferative capacity and cytokine production in response to specific antigenic stimulation [26]
To analyze antigen-specific CD8 T cells in a nonhuman primate model, we studied seven Mamu-A*001 rhesus macaques among our twenty animals

Summary

Introduction

Programmed cell death 1 (PD-1) is a member of the CD28 family, which modulates T cell function [1] and is primarily upregulated on the surface of CD4 and CD8 T cells upon activation [2]. PD-1 interacts with its ligands PD-L1 or PD-L2 and this engagement induces tyrosine phosphorylation of the cytoplasmic domain of PD-1 This process recruits tyrosine phosphatases which dephosphorylate TCR proximal kinases to limit the TCR/CD28 signal transduction. Similar findings have been observed in other chronic viral infections, such as human T cell lymphotrophic virus (HTLV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) [3,4,5,6] and more recently in patients with various forms of advanced cancers [7,8] These findings indicate that the expression of PD-1 by T cells distinguishes physiologically ‘‘activated’’ cells from ‘‘exhausted’’ T cells as a result of persistent antigenic stimulation

Methods

Results

Conclusion