Role of the PD-1 pathway in the immune response

Abstract

Understanding immunoregulatory mechanisms is essential for the development of novel interventions to improve long-term allograft survival. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, have emerged as critical inhibitory signaling pathways that regulate T cell response and maintain peripheral tolerance. PD-1 signaling inhibits alloreactive T cell activation, and can promote induced regulatory T cell development. Furthermore, the upregulation of PD-L1 on nonhematopoietic cells of the allograft may actively participate in the inhibition of immune responses and provide tissue-specific protection. In murine transplant models, this pathway has been shown to be critical for the induction and maintenance of graft tolerance. In this review, we discuss the current knowledge of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential in transplantation.

Figure 1. Effect of PD-1 signaling in T cells

PD-1 signaling dephosphorylates proximal signaling molecules and augments PTEN expression, inhibiting PI3K and AKT activation. The consequences include decreased T cell proliferation, cytokine production and cell survival. PD-1 inhibition can be overcome by strong TCR signaling, CD28 signaling or IL-2 signaling (not shown). SHP2, protein tyrosine phosphatase; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; AKT, serine/threonine protein kinase; PIP3, Phosphatidylinositol (3,4,5)-triphosphate.

Figure 2. Costimulatory signaling network

Integration of both positive and negative costimulatory signals during and after initial T cell activation will determine the fate and intensity of the alloimmune response. The complexity of the costimulatory network is exemplified by the potential effects of B7-1 targeting (such as accomplished by CTLA-4-Ig) – while blockade of B7-1 decreases positive costimulatory signaling through CD28 (A), it may affect two inhibitory signaling pathways, preventing B7-1 engagement of CTLA-4 (B) and PD-L1 (C). Dashed line represent the still controversial issue of reverse signaling through PD-L1 or PD-L2.

Figure 3. PD-1: PD-L1 signaling in allograft tolerance

This figure illustrates some of the potential interactions of this pathway in lymphoid organs and in a cardiac allograft. (A), Tolerogenic DCs interact with naïve T cells and may induce either alloantigen-specific Tregs (iTregs) or decreased activation of effector T cell (T eff), depending on the presence (or absence) of TGF-β. (B), After activation by DCs in secondary lymphoid organs, alloantigen-specific effector T cells migrate to the graft where initial interaction with PD-L1 in the endothelium might inhibit T effector responses. Additional T eff cells that infiltrate the graft may be suppressed by iTregs or local cells expressing PD-L1 (APCs or non-hematopoieitic cells). Whether PD1/PDL1 on iTregs play a significant role in the direct suppression of T eff remains to be determined. Other potential costimulatory interactions are not depicted in this figure for simplicity.