Programmed Death 1 Lives Up to Its Reputation in Active Tuberculosis

Abstract

Programmed death 1 (PD-1; CD279), also known as programmed cell death protein 1 (PDCD-1), is a cell surface receptor of the immunoglobulin superfamily found on immune effector cells. It belongs to the extended CD28/CTLA-4 family of T-cell regulators and is expressed by a range of immune cells, including B cells, natural killer cells, and monocytes. Binding of PD-1 to one of its ligands, PD ligand 1 (PD-L1) or PD-L2, on antigen-presenting cells (APCs) is known to negatively regulate T-cell receptor signaling and inhibit T-cell activation [1]. In this issue of the Journal, Singh et al [2] demonstrate that the coinhibitory receptor PD-1 and the PD ligands are expressed on higher percentages of peripheral blood mononuclear cells (PBMCs) of patients with active tuberculosis than those of healthy controls in an area of tuberculosis endemicity. The expression of PD-1 on T cells is upregulated following in vitro stimulation with Mycobacterium tuberculosis antigens, and the PD-1 blockade in vitro enhances interferon γ (IFN-γ) and interleukin 2 production by specific T cells and rescues them from undergoing apoptosis. Of particular significance, the authors demonstrate during a 1-year follow-up period a significant decrease in the frequency of PD-1–expressing T cells after successful antituberculosis treatment that led to restoration of the M. tuberculosis–specific T-cell cytokine response in vitro. These data substantiate the role of PD-1–PD-L pathways in the inhibition of T-cell responses in patients with active tuberculosis. Optimal T-cell activation during infection requires 2 signals. The first signal is generated by T-cell–receptor recognition ofpeptide–majorhistocompatibilitycom