The PD-1 pathway in tolerance and autoimmunity

Abstract

Regulatory T cells (Tregs) and the PD-1: PD-ligand (PD-L) pathway are both critical to terminating immune responses. Elimination of either can result in the breakdown of tolerance and the development of autoimmunity. The PD-1: PD-L pathway can thwart self-reactive T cells and protect against autoimmunity in many ways. In this review, we highlight how PD-1 and its ligands defend against potentially pathogenic self-reactive effector T cells by simultaneously harnessing two mechanisms of peripheral tolerance: (i) the promotion of Treg development and function and (ii) the direct inhibition of potentially pathogenic self-reactive T cells that have escaped into the periphery. Treg cells induced by the PD-1 pathway may also assist in maintaining immune homeostasis, keeping the threshold for T-cell activation high enough to safeguard against autoimmunity. PD-L1 expression on non-hematopoietic cells as well as hematopoietic cells endows PD-L1 with the capacity to promote Treg development and enhance Treg function in lymphoid organs and tissues that are targets of autoimmune attack. At sites where transforming growth factor-beta is present (e.g. sites of immune privilege or inflammation), PD-L1 may promote the de novo generation of Tregs. When considering the consequences of uncontrolled immunity, it would be therapeutically advantageous to manipulate Treg development and sustain Treg function. Thus, this review also discusses how the PD-1 pathway regulates a number of autoimmune diseases and the therapeutic potential of PD-1: PD-L modulation.

Figures

Fig. 1. Relative expression of PD-1 and its ligands

(A) Comparison of expression of PD-1, PD-L1 and PD-L2 on immune and non-immune cells in naive or activated states. (B) Factors that regulate expression of PD-1, PD-L1, and PD-L2. Regulation of expression on specific cell types is discussed in detail in the text. There are some differences in expression of human and mouse PD-1, PD-L1, and PD-L2 expression. Murine expression is summarized in this figure. Expression of human PD-L1 differs from mouse PD-L1 in that human PD-L1 is primarily an inducible molecule.

Fig. 2. PD-1 signaling

Ligation of TCR and PD-1 leads to tyrosine phosphorylation (P) of the ITIM and ITSM of PD-1. Binding of the ITSM by SHP-1 or SHP-2 results in the dephosphorylation of proximal signaling molecules and augmentation of PTEN expression. This effectively attenuates the activation of the PI3K and Akt pathways. PD-1 signaling may result in decreased T-cell proliferation, survival, protein synthesis, and IL-2 production. (Red arrows and text indicate consequence of PD-1-mediated signaling)

Fig. 3. PD-L1-mediated conversion of naive T cells to regulatory T cells

PD-1 upregulation upon TCR stimulation mediates PD-1: PD-L1 interaction between the T cell and the APC (or artificial APC consisting of epoxy bead coated with anti-CD3, anti-CD28, PD-L1-Ig and control-Ig) in the presence of TGF-β. When PD-L1 is present on the bead, iTreg conversion is enhanced approximately twofold (left). Similarly, a twofold enhancement of conversion is observed when using WT APCs as compared to PD-L1−/− APCS (right). Adapted from Francisco et al., J Exp Med 2009.

Fig. 4. Differential fates of naive T cells following PD-1 ligation

(A) Upon TCR engagement of a naive T cell, PD-1 and PD-L1 are upregulated. (B) The PD-L1 pathway inhibits the downstream PI3K/AKT pathway in naive T cells resulting in functional inactivation of naive T cells and inhibition of effector T-cell differentiation and function. (C) In the presence of TGF-β, the PD-1 pathway attenuates the PI3K/AKT pathway, preferentially biasing naive T-cell programming towards iTreg development and survival.

Fig. 5. Functions of the PD-1 pathway on Tregs

(i) PD-L1-expressing DCs may induce the conversion of naive T cells to Foxp3+ iTregs. Upon interaction with a PD-L-bearing DC, Tregs may condition the DC towards tolerogenicity. (ii) PD-L1-expressing Tregs may sustain Foxp3 Treg expression and effector function in other Tregs. (iii) Tregs can also directly suppress autoreactive T effectors (limit IL-2 production, prevent cell cycle progression, negatively influence stable DC: Teff interactions, etc.) or (iv) promote the contra-conversion of T effectors to iTregs.

Fig. 6. The PD-1:PD-L pathway can regulate the dynamics between effector and regulatory T cells during multiple stages of autoimmune disease progression

This figure illustrates consequences of these interactions in lymphoid organs and peripheral tissues. (A) PD-L1-expressing DCs stimulate PD-1 expression on naive T cells. PD-L1: PD-1 interactions limit T-effector cell expansion and survival. (B) In the presence of TGF-β, PD-L1-expressing DCs can promote the development of iTregs. (C) Tregs may restrain the magnitude of the immune response by inhibiting both DC and effector T-cell functions. (D) Activated T effector cells migrate to sites of inflammation where interaction with (i) PD-1-expressing Tregs or (ii) PD-L1 expressing target cells can (a) directly inhibit T-effector responses or may( b) facilitate the ‘contra-conversion’ of T effectors toward iTregs within the target organ. Additional cell types expressing PD-L1 such as the vascular endothelium and stromal cells may also influence T-effector cells but are not depicted in this figure for simplicity.

Fig. 7. Mechanisms of PD-1-mediated T-cell tolerance

PD-L1 ligation of PD-1 following TCR stimulation results in two possible T-cell fates: diminished T-effector responses and augmented iTreg development, thus tipping the balance towards immunologic tolerance.