Immune Checkpoints in Solid Organ Transplantation

Abstract

Allogenic graft acceptance is only achieved by life-long immunosuppression, which comes at the cost of significant toxicity. Clinicians face the challenge of adapting the patients' treatments over long periods to lower the risks associated with these toxicities, permanently leveraging the risk of excessive versus insufficient immunosuppression. A major goal and challenge in the field of solid organ transplantation (SOT) is to attain a state of stable immune tolerance specifically towards the grafted organ. The immune system is equipped with a set of inhibitory co-receptors known as immune checkpoints (ICs), which physiologically regulate numerous effector functions. Insufficient regulation through these ICs can lead to autoimmunity and/or immune-mediated toxicity, while excessive expression of ICs induces stable hypo-responsiveness, especially in T cells, a state sometimes referred to as exhaustion. IC blockade has emerged in the last decade as a powerful therapeutic tool against cancer. The opposite action, i.e., subverting IC for the benefit of establishing a state of specific hypo-responsiveness against auto- or allo-antigens, is still in its infancy. In this review, we will summarize the available literature on the role of ICs in SOT and the relevance of ICs with graft acceptance. We will also discuss the possible influence of current immunosuppressive medications on IC functions.

Keywords: immune checkpoints; immunotherapy; organ transplantation; tolerance.

Figure 1

Regulation of conventional T cell activation by CTLA-4. Priming of naïve T cells requires CD28 co-stimulation, which engages multiple stimulatory pathways: PI3K-AKT, PKCθ, and Ras. CTLA4 binds with higher affinity to CD28 ligands CD80 and CD86, thereby disrupting CD28 signaling. Further, the phosphatases SHP2 (SH2 domain-containing tyrosine phosphatase 2) and PP2A (serine/threonine protein phosphatase 2A), bound to the intracellular tail of CTLA4, directly inhibit proximal CD3 signaling.

Figure 2

Role of IC expression on regulatory T cells.

Figure 3

Regulation of conventional T cell activation by PD-1. PD-1 recruits the phosphatase SHP2 to inhibit the CD3 signaling cascade at the level of ZAP-70 phosphorylation and PI3K activation. It also inhibits Ras. SHP-2 can also recruit BATF to inhibit, directly, effector gene transcription. PD-1 may also interfere with CD28 signaling.

Figure 4

Regulation of conventional T cell activation by Tim-3. Tim- interacts with HLA-B-associated transcripts 3 (BAT3), which maintain lck in an activated form and promote CD3 signaling. In the presence of Gal-9, BAT3 is released from Tim-3, resulting in inhibition of CD3 signaling via an unidentified mechanism.

Figure 5

Regulation of conventional T cell activation by BTLA. BTLA interacts with HVEM at the surface of APC. Once activated, it recruits the phosphatases SHP1 and SHP2 to inhibit the proximal CD3 signaling. Further, HVEM is also able to transduce inhibitory signals to the APC (not depicted).

Figure 6

Regulation of conventional T cell activation by TIGIT. CD226 is a major co-stimulatory molecule for T cells. TIGIT binds to the same ligand (CD155, CD112, or CD113) with higher affinity, thereby disrupting the CD226 signaling. TIGIT also mediates direct inhibitory signaling through the recruitment of SHP1/SHP2. Finally, reverse signaling through TIGIT ligands may induce IL-10 production by DCs, making them tolerogenic.

Figure 7

Regulation of conventional T cell activation by CD244. Upon binding to its ligand CD48 (either through trans- or cis-interactions), CD244 recruits the adaptor protein EAT-2, resulting in inhibition of proximal CD3 signaling.

Figure 8

Regulation of conventional T cell activation by LAG-3. The putative mechanisms of action of LAG-3 primarily involve a repetitive C-terminal EP motif, responsible for disrupting co-receptor–lck interactions, in part through Zn²⁺ sequestration.