PD-1 and its ligands in tolerance and immunity

Abstract

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.

Figure 1

Comparison of expression of PD-1, PD-L1, PD-L2, and B7-1 on human and mouse cells. PD-1, PD-L1, PD-L2, and B7-1 are expressed on a wide range of human (–, , , , , , , –149) and mouse cells (, , , , , , , , , –153).

Figure 2

Ligation of PD-1 dampens TCR signaling but can be overcome by CD28 costimulation. PD-1 engagement on the cell surface leads to phosphorylation of PD-1 cytoplasmic tyrosines and increases SHP-2 association with the ITSM of PD-1. Recruitment of SHP-2 dephosphorylates signaling through the PI3K pathway and downstream signals through Akt. PD-1 ultimately decreases induction of cytokines, such as IFN-γ, and cell survival proteins, such as Bcl-xL. When signaling through CD28 is delivered at the same time as PD-1 and TCR ligation, inhibitory effects can be overcome, and cytokine production and cell survival is enhanced.

Figure 3

B7-1:PD-L1 interaction expands pathways in the B7:CD28 family. Recent data demonstrate that PD-L1 and B7-1 productively interact on T cells and can deliver bidirectional inhibitory signals. The identification of these costimulatory molecules as binding partners increases our understanding of the interactions that can occur on T cells and APCs and raises the possibility that PD-L1:B7-1 binding may not only deliver signals when ligated, but may also serve to segregate binding away from previously identified receptors (PD-1, CD28, CTLA-4). IgV-like regions are depicted in blue and IgC-like regions in green, while tyrosine-containing signaling motifs are depicted by Ys.

Figure 4

PD-L1 is upregulated on breast tumor, but not normal, cells Immunohistochemical staining (brown) of a breast ductal carcinoma showing high expression of PD-L1 on neoplastic tissue (thick arrow) and low expression on adjacent normal tissue (thin arrow) (figure kindly provided by David Dorfman, Brigham and Women’s Hospital). Note that lymphocytes are more abundant in normal tissue areas than in cancer cell nests.