Immune Checkpoints in Solid Organ Transplantation: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Emmanuel TREINER.

The immune system spontaneously recognizes and destroys foreign cells and organs when grafted into a genetically different individual. Organ transplantation is only successful because of the use of life-long immunosuppressive medications, which comes at the cost of severe toxicities. Thus, a major breakthrough in transplantation would be to be able to educate the immune system to accept grafted organs in the long term. A possible way to do that would be to exploit a physiological retro-control of the immune cells, which is based on the timely and coordinated expression of cell-surface receptors with inhibitory activities. In cancer, blocking these receptors (or Immune Checkpoints) boosts the anti-tumor functions of certain immune cells (the T-lymphocytes), with highly significant clinical benefits. Thus, it is likely that opposite actions, such as increasing the expression or the function of these receptors, would result in the dampening of the immune response against foreign organs.

  • immune checkpoints
  • organ transplantation
  • tolerance
  • immunotherapy

1. Introduction

Immune checkpoints (IC) are cell-surface-expressed molecules regulating leucocyte functions. They are mostly found at the surfaces of lymphocyte subsets, but some of them can be expressed on other leucocyte subtypes or even on non-immune cells. Their inhibitory functions are mostly induced upon interaction with their cognate ligand(s), although some cell-autonomous activities have been described. ICs can have one or more specific ligands, which may themselves be more or less widely expressed, both within and outside the immune system. There are several described ICs, the most widely studied being CTLA-4, PD-1, TIGIT, TIM-3, BTLA, and LAG-3 [1,2,3][1][2][3]. These proteins play physiological regulatory functions through transient activation-induced expression, allowing the fine-tuning of cell activation. However, in chronic settings, such as chronic viral infections or cancer, the sustained expression of multiple ICs is associated with metabolic and epigenetic changes, which favor hypo-responsiveness and antigenic persistence [4,5][4][5]. This cell dysfunction, sometimes referred to as “exhaustion”, may be reversed through the blockading of the interaction between ICs and their ligands using monoclonal therapeutic antibodies. Indeed, immune checkpoint blockade (ICB) has emerged in the recent years as a revolutionary approach to anti-tumor therapy and [6], more anecdotally, as anti-infectious immune therapy [7]. Marketed ICBs target CTLA4 (Ipilimumab) or PD-1 (Nivolumab, Pembrolizumab, Cémiplimab) and its ligand PD-L1 (Avélumab, Atézolizumab, Durvalumab). However, multiple ICBs targeting other ICs (or their ligands) are under development, and several are currently being tested in clinical trials for cancers (clinicaltrials.gov).

2. The Role of Immune Checkpoints and Their Ligands in Solid Organ Transplantation

2.1. CTLA-4

Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4, or CD152) was the first described inhibitory molecule for T cells [19][8]. CTLA4 has gained incredible attention after the demonstration that blocking its interactions with its ligands can be highly beneficial to subsets of patients with cancer, paving the way for the immune therapy of cancer with immune checkpoint inhibitors (ICIs) [20,21][9][10]. The administration of such therapies in solid-organ-transplant patients was associated with a dramatic increase risk of acute, severe TCMR [22][11]. The paramount importance of CTLA-4 in regulating the immune system is demonstrated both by the phenotype of CTLA4 insufficiency (as well as LRBA deficiency, which inhibits CTLA4 expression by disrupting its recycling) in humans [13][12] and the early deaths of CTLA-4 knock-out (KO) mice [23][13]. CD80 (B7-1) and CD86 (B7-2) are CTLA-4-binding partners expressed on the surfaces of professional antigen-presenting cells. CTLA-4 functions at least at two separate levels: first, it is transiently expressed in activated T cells and disrupts CD28/B7 interactions, thereby acting as a physiological inhibitor of co-stimulation (Figure 1). In this respect, CTLA-4 is assumed to exert its regulatory effects at the time of T cell priming in lymphoid organs. Second, CTLA-4 is also strongly and constitutively expressed by Foxp3+-regulatory T cells (Tregs), and is crucial to their functions (Figure 2) [24][14]. This dual action of CTLA-4 is a source of complexity and difficulties to disentangle the cellular mechanisms at play in specific conditions [25][15]. This roadblock has been partially resolved through the generation of cell-type-specific and conditional KO mice. Indeed, the Treg-specific deletion of CTLA-4 is sufficient for mice to develop a fatal lymphoproliferative disease, showing the crucial role of CTLA-4 for the Treg-mediated regulation of conventional T (Tconv) cells in vivo [26][16]. On the other hand, two groups developed conditional KO to study the consequences of CTLA deletion at an adult age [27,28][17][18].
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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.
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Figure 2.
Role of IC expression on regulatory T cells.
Another difficulty lies in the structure similarity and sharing of binding partners of CTLA-4 with the co-stimulatory CD28 molecule, which makes it difficult to analyze them separately. To overcome the drawbacks of traditional CTLA-4 models, some groups managed to generate CD28-specific antagonists, leaving CTLA-4 alone for analysis. They were then able to show that blocking CD28 significantly delays the acute rejection of kidney and cardiac transplants in baboons and macaques, respectively [29][19].
There are three common polymorphisms in the CTLA-4 gene, which result in lower CTLA-4 expression and/or the decreased production of a soluble form of CTLA-4, which itself leads to increased T cell activation [32][20]. These polymorphisms have been studied as possible influencers of acute rejection with mixed conclusions. For example, the CTLA-4 rs3087243*G allele was found to be protective against TCMR in kidney transplant recipients (KTRs) [33][21]. Other polymorphisms were studied but with no definitive conclusion as to their effect on transplantation [34][22]. 

2.2. PD-1

Programmed Death-1 (PD-1) is a major inhibitory receptor expressed on subsets of memory cells, activated and exhausted T cells, and Tregs (Figure 2). It can be also expressed on other cell types such as NK cells, B cells, and some myeloid cells. PD-L1 and PD-L2 are PD-1 ligands, the former expressed by multiple cell types and the latter primarily by hematopoietic cells such as DCs. In mature T cells, PD-1 inhibits T cell activation by disrupting both the CD3 and CD28 signaling cascades, thereby controlling proliferation and effector functions (Figure 3).
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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.
Similar to anti-CTLA-4 antibodies, the use of marketed ICI targeting the PD-1 pathway is associated with an increased risk of acute organ rejection, strongly suggesting that PD-1 physiologically regulates alloreactive T cells in the setting of transplantation [22][11]. 
The PD-1 pathway has been the subject of a number of studies aimed at deciphering its role in graft survival and how it could be targeted to dampen rejection. More than 20 years ago, Özkaynak et al. analyzed the effect of PD-1 in a mouse model of cardiac transplantation. Whereas targeting PD-1 with PDL1-Ig fusion proteins alone had no effect on graft rejection, it strongly synergized with IS-targeting T cells, such as Cyclosporin A (CsA) or rapamycin (Rapa), to promote graft survival [42][23].
These data suggest that the inhibitory function of PD-1 may not be sufficient by itself to protect against acute rejection; however, it displays a cumulative effect with either T-cell-targeting IS or the absence of co-stimulation and then becomes able to modulate acute and chronic rejection. PD-1 blockade also accelerates heart rejection in fully mismatched animals, but only in the absence of CD28 co-stimulation [45][24]. Chimera experiments demonstrated the importance of PD-L1 expression on non-hematopoietic donor cells [46][25] for protection against rejection.
The PD-1/PD-L1 pathway may play a prominent role in controlling allograft vasculopathy. In vitro, smooth muscle cells express PD-L1 upon IFNγ treatment, and its blockade amplifies their proliferation induced by splenocytes. PD-L1 is also expressed in SMC from graft arteries in vivo, and anti-PD-L1 treatment increases the thickening of the intima [47][26].
In line with this, the artificial expression of PD-L1 by glomerular endothelial cells could delay graft damages upon acute rejection in a rat model of kidney transplantation. This effect was associated with decreased T cell infiltration except for an increased frequency of regulatory T cells [49][27]. PD-L1 may also be involved in protecting renal tubular epithelial cells (TECs) from alloreactive T cells [50][28]. TECs express PD-L1 under inflammatory conditions, and this PD-L1 is then able to inhibit alloreactive CD4 and CD8 T cells, at least in vitro. Biopsy analyses show that whereas PD-L1 expression is indeed induced during rejection, it is not sufficient to fully protect against damage.

2.3. Tim-3

Constitutively expressed by dendritic cells and regulatory T cells [57][29], T-cell-immunoglobulin-and-mucin-containing protein-3 (Tim-3, or CD366) is induced early after activation on conventional T cells [58][30]. Tim-3 expression by Tregs may play a major role in their suppressive function, at least in specific contexts [59,60][31][32]. In contrast to CTLA-4 or PD-1, Tim-3 expression is confined to the Th1 and Th17 cell subsets of CD4+ T cells, and to IFNγ-producing -CD8+ T cells [58,61,62][30][33][34]. These observations suggest a specific role for Tim-3 in the regulation of the more inflammatory subsets of T cells. Another peculiarity of Tim-3 is the existence of several ligands, including galectin-9 (Gal9), Carcinoembryonic-antigen-related cell-adhesion molecule 1(CEACAM-1), Phosphatidylserine (PtdSer), and high-mobility group box 1 (HMGB1), showing wide cellular and tissue expression. However, Gal9 seems to be the major Tim-3 ligand. Tim-3 signaling directly interferes with the CD3 signaling cascade. However, the mechanisms by which Tim-3 regulates T cell functions are poorly understood; the current hypotheses propose that Tim-3 displays a dual stimulatory/inhibitory function depending on the interaction with an intra-cytoplasmic signaling adaptor, Bat3 (Figure 4).
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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.
It was shown 20 years ago, in a seminal paper, that Tim-3 was involved in a model of transplantation tolerance to islet allografts induced by a combination of donor-specific transfusion and CD40L blockade [67][35]. Similarly, blocking Tim-3 largely accelerated acute rejection in a murine model in the absence of CD28/B7 co-stimulation [57][29]. 

2.4. BTLA

B and T Lymphocyte Attenuator (BTLA) belongs to the CD28 superfamily of receptors and is broadly expressed on T, B, and dendritic cells. In contrast with most inhibitory receptors, BTLA4 is highly expressed on quiescent, naïve T cells, and its expression tends to decrease with activation. BTLA ligand is the Herpes Virus Entry Mediator (HVEM), a member of the TNF-R superfamily expressed on various leucocyte subsets. BTLA regulates cell functions in part through the ITIM domain encoded in its cytoplasmic tail, interfering with T cell signaling (Figure 5) [74][36].
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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).
It was shown as early as 2005 [75][37] that BTLA has a dominant role in the acceptance of partially mismatched heat allografts in a mouse model as alloreactive cells infiltrating the grafted heart show strong BTLA expression. BTLA expression is decreased in KTR with biopsy-proven acute rejection, and its overexpression was shown to be protective against rejection in a rat model of KT [76][38]. BTLA acts primarily to dampen alloreactive CD4 T cell activation, although a detailed description of the BTLA pattern of expression in this model is lacking. Graft survival with BTLA overexpression was further sustained with the use of a concurrent blockade of a major co-stimulatory pathway with belatacept [77][39], highlighting, again, the strong synergy between IC signaling and co-stimulation blockade.

2.5. TIGIT

TIGIT (T cell immunoreceptor with Ig and ITIM domains) has recently been implicated in events linked to transplant tolerance and rejection and as potential target for immunotherapy. TIGIT is expressed on subsets of memory T cells, Tregs, and NK and B cells (Figure 2). It binds to three different ligands, CD155, CD112, and CD113, with different affinities. Importantly, TIGIT shares the same ligands with CD226 (DNAM-1), a co-stimulatory receptor expressed on T and NK cells (Figure 6). TIGIT and CD226 thus compete for ligand binding, with TIGIT winning the race owing to its higher affinities for these ligands. TIGIT may regulate T cell functions through multiple mechanisms as its expression directly inhibits T cell signaling, but it also induces IL-10 production by DCs after interacting with their ligands [11,78,79,80,81][40][41][42][43][44].
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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.

2.6. CD244

CD244 (SLAMF4), also known as 2B4, belongs to the SLAM (Signaling Lymphocytic Activating Molecules) family. It is mostly expressed on NK cells but also on subsets of CD8+ T cells and other leucocyte subsets. CD244 binds CD48, another SLAM, through not only trans but also cis interactions (Figure 7). CD244 is peculiar in its ability to transmit both stimulatory or inhibitory signals in a process that may be regulated by binding to different adaptor-signaling molecules (SAP or EAT-2) [90,91][45][46].
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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.

2.7. Other Inhibitory Receptors

Lymphocyte Activation Gene-3 (LAG-3, or CD223) was the second inhibitory co-receptor discovered, after CTLA-4 [93][47]. Like many others, it is upregulated upon TCR-mediated activation on T cells and expressed on subsets of Tregs (Figure 2). Similarly to PD-1, initial studies showing the importance of LAG-3 in Treg functions [94][48] were balanced by more recent work suggesting that it may, in fact, limit their regulatory functions [95][49]. Structurally related to the CD4 molecule, it binds MHC class II molecules as well (Figure 8), although other ligands have also been recognized (recently reviewed in [96][50]). LAG-3 has been suggested to control GVHd in allogenic stem cell transplantation [97][51] and only one recent paper (not peer-reviewed yet) also suggests it may function in organ transplantation.
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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.

3. T Cell Exhaustion in Solid Organ Transplantation

Lymphocyte exhaustion has been described, initially, as a state of CD8 T cell hypo-responsiveness developing in the face of chronic viral infection in mice [105][52]. This observation has been extended to human chronic viral infections and, mostly, cancer, where lymphocyte exhaustion is thought to explain the inefficiency of tumor-infiltrating lymphocytes in actually clearing cancer cells [4]. A wealth of studies have described the epigenetic, metabolic, phenotypic, and functional features associated with exhaustion in various settings [5].
The most recent theories postulate that exhaustion actually reflects a gradient of differentiation states for T cells, ranging from early (or precursors) to late-exhausted, with a range of dysfunctional features, which may in fact be a way for T cells to adapt to chronic antigen exposure. In other words, when T cells face an antigen they are not able to clear, they engage in a differentiation process, which allow them to persist, control—to some extent—the antigenic insult, and avoid overt immunopathology [110][53]. Theoretically, the continuous presence of allo-antigens in SOT may induce a state of exhaustion in alloreactive T cells. As a matter of fact, it has long been shown that alloreactive T cells from some transplanted patients evolve into a state of donor-specific hypo-responsiveness over time, which correlates with better graft function [111,112,113][54][55][56]; the mechanisms behind this are not clear [85,114,115][57][58][59]. The appearance of exhaustion in donor-specific alloreactive T cells could be indicative of some level of adaptation of the recipient immune system to a foreign tissue and open the way to new strategies to attain tolerance to transplanted organs. Ten years ago, an intriguing paper showed that exhaustion in CD4 T cells mediated allograft tolerance in a model of cardiac transplantation, which could be reversed by anti-PD-1 [116][60].

4. Interactions between Immunosuppressive Drugs and IC Expression and Function

It is highly likely that immunosuppressive drugs may have an impact on IC expression and T cell exhaustion. In the mouse model of chronic LCMV infection (a model for antigen-specific exhaustion), a complex interplay between PD-1 and mTOR is demonstrated, whereby rapamycin inhibits the effect of PD-1 blockade [120][61]. This suggests that mTOR regulates T cell exhaustion in this model. However, blocking mTOR at the beginning of a T cell response increases the response and inhibits exhaustion [121][62]. The chronic administration of rapamycin to healthy aged mice decreases the expression of PD-1 and LAG-3 and increases proliferative capacities, suggesting the reduction of “natural” exhaustion [122][63]. On the other hand, another widely used IS agent, mycophenolate mofetil (MMF), may show an opposite effect. Several co-IRs (PD-1, LAG3, TIGIT…) displayed higher expression on blood Treg cells from stable liver transplant recipients treated with tacrolimus (a CNi) + MMF compared to patients treated with tacrolimus only, suggesting that MMF increases IR expression [128][64]. Further, Tregs from patients treated with the same regimen were more effective at inhibiting T cell proliferation [129][65], and this effect was partially abrogated when treated with a combination of anti-TIGIT and anti-PD-1.

5. Harnessing Inhibitory Pathways in Solid Organ Transplantation

Beyond the potential role of ICs in predicting the outcomes, several molecules harnessing ICs are currently in the pipe. The success of IC blockade in subsets of cancer patients has prompted a major endeavor in both academic and industry groups to develop new strategies to overcome T cell exhaustion. The reverse action may be efficient in organ transplantation. Indeed, targeting co-stimulatory pathways such as CD80/86 with belatacept has demonstrated interesting results with respect to the prevention of acute and chronic allograft rejections. It is noteworthy that most murine studies showing the role of ICs such as PD-1 in regulating chronic organ rejection have been performed alongside the blockading of co-stimulatory pathways; the manipulation of inhibitory pathways in the presence of intact co-stimulatory signaling has often yielded disappointing results. This observation may simply reflect the fact that blocking co-stimulation while enhancing inhibition is probably more efficient for the regulation of T cell activation as compared with targeting only one of these pathways. However, it is important to recall that insufficient help from CD4+ is one of the processes leading to CD8+ T cell exhaustion [106,130][66][67]. Thus, combining IC activation with co-stimulation blockade may be a synergistic approach because the latter would induce or contribute to differentiating T cells towards a hypo-responsive, exhausted state.  

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