ReviewRecent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity
Introduction
Autoimmune diseases are a heterogeneous group of ‘common complex disorders’ [1] affecting various organs or systems. Although defined as non-Mendelian, they often present with familial clustering. In their etiopathogenesis gene–environment interactions play a dominant role [2]. These disorders, taken together, approximately affect 5% of the population (reviewed (rev.) in [3]). Notably, as a result of shared pathophysiological mechanisms, patients affected by one autoimmune disease have an increased susceptibility to other autoimmune conditions (rev. in [4]).
The incidence of autoimmunity is increasing worldwide [2]. Immunological abnormalities can precede months to years the initial symptoms and clinical diagnosis and, with the genetic risk factors, are relevant to prediction strategies of the disease.
Experimental studies demonstrate that autoimmunity derives from the escape of antigen-specific autoreactive T cells in the periphery from the thymus in the perinatal age [4]. This is caused by a failure in promiscuous thymic expression of peripheral organ-specific antigens in the same organ (rev. in [4]). Among the cellular players, T helper (Th) cells [5], that escaped mechanisms of self-tolerance, initiate inflammation and provide help to autoreactive B cells [6] mediated by proinflammatory cytokines. The activation, expansion and subsequent differentiation of mature B cells in plasma cells producing autoantibodies further contribute to tissue damage. Th cells, when encountering the self- or cross-reactive antigen, activate, expand and differentiate into Th1, Th2 subtypes, regulatory T (Treg) and Tr1 cells (rev. in [7]). Th1 and Th2 cells secrete two different and mutually inhibitory pathways of cytokines. Th1 cells secrete interleukin 2 (IL-2) and interferon gamma (IFN-γ), while Th2 cells secrete interleukin 4 (IL-4), interleukin 5 (IL-5) and interleukin 10 (IL-10). Recently the CD4+ T cell subset Th17 was shown to have a pivotal role in the pathogenesis of rheumatoid arthritis (RA) and multiple sclerosis (MS) (rev. in [4]). These cells produce interleukin 17 (IL-17), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) [8]. B regulatory cells expressing CD5, a negative regulator of T cell receptor (TCR) and B cell receptor (BCR) signaling, protect against autoimmunity through the production of IL-10. CD5 B cells, namely B1 cells, were found to express IgM in greater quantities than IgG [9]. IgM are elevated in several autoimmune conditions, although it remains unclear whether these antibodies have a role in the loss of immunological tolerance or whether they simply represent epiphenomena.
Information regarding the etiopathogenesis and the genetic susceptibility to autoimmunity has rapidly increased with the advances in immunogenetics over the past years [4]. As recently shown by genetic mapping studies, multiple genetic loci are responsible for T1D, systemic lupus erythematosus (SLE), MS, inflammatory bowel disease (IBD), RA and psoriasis.
In autoimmune diseases characterized by the involvement of multiple subtypes, a common genetic allele association was first demonstrated in the 1970s with the major histocompatibility complex (MHC) region encoding human leukocyte antigens (HLAs) [10]. With the advent of genome-wide linkage, candidate gene and genome-wide association studies [10], in addition to HLA, several single nucleotide polymorphisms (SNPs) were discovered that putatively underlie the pathogenesis of autoimmunity [3]. In citing examples of candidate common susceptibility genes involved in immune regulation, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) suppresses T cell activation, forkhead box protein 3 (FoxP3) is involved in Treg differentiation, the IL-2Rα/CD25 gene also affects the development and function of Treg, and the TNF-α gene, located on chromosome 6p21.3, is at the basis of the increased risk for the association of T1D and autoimmune thyroid disease. Among the others, protein tyrosine phosphatase non-receptor type 22 (PTPN22) encoding lymphoid tyrosine phosphatase (Lyp) protein affects the TCR signaling pathway (rev. in [11]).
New molecules and pathways with pivotal functions in regulating immunological tolerance and autoimmunity were discovered in recent years. In this review, we focus on the physiological role exerted by the programmed cell death 1 (PD-1, CD279) receptor and its ligands [PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273)] [12] in regulating T cell activation, tolerance and immune-mediated organ damage. This pathway exerts inhibitory functions in chronic viral infections, tumors, with special relevance to autoimmunity. Both PD-1 and PD-L1 are found expressed not only on T cells, but also on B cells, macrophages and some types of dendritic cells (DCs). The dynamics of PD-1 pathway and Treg has been in particular elucidated in explaining its inhibitory function. Thus, the pathway may exert different potential immunological interactions. Its altered function has been reported in experimental models of autoimmunity and pathogenetic polymorphisms were already identified in several human autoimmune conditions, in certain ethnic groups. Finally, we discuss possible clinical applications of PD-1/PD-L1 manipulation in autoimmunity.
Section snippets
The physiological role of PD-1 in lymphocyte activation
The activation of a T cell is induced upon the interaction of the TCR with the specific peptide/MHC; the co-stimulatory signal occurs through receptors present on the T cell surface interacting with their selective ligands on the antigen presenting cells (APC) [13]. When co-stimulation is not engaged and signaling occurs through TCR alone, a state of anergy or apoptosis is induced [13].
Among the co-stimulatory receptors, molecules belonging to the immunoglobulin (Ig) superfamily CD28, binding
PD-1 signaling and Treg
Of note PD-1 and PD-L1 were detected on Treg [12], characterized by the expression of FoxP3 [43], [44], [45], [46]. Treg can be divided into two subpopulations: naturally occurring (nTreg), which develop in the thymus, and adaptive (iTreg), generated in the periphery from CD4+ FoxP3− naive T cells. In vitro experiments demonstrated the conversion of naive T cells into iTreg upon stimulation with TGF-β and IL-2 [47], [48], [49], [50]. Treg are involved in the regulation of peripheral tolerance
Role of PD-1/PD-L1 pathway in the establishment and maintenance of tolerance
PD-1 and its ligands are involved in the modulation of both central and peripheral tolerance [12], although opposing effects induced by PD-1 ligands are reported, some studies supporting inhibition of immune response [62], [63], while others their activatory role [64], [65].
In particular, PD-1 plays a critical role at several levels of thymocyte development, by regulating signaling thresholds during positive selection [66]. As a consequence of the loss of PD-1 or PD-L1, the number of DP (CD4+
PD1 studies in experimental animal models of autoimmunity
The role of the PD-1/PD-L1 pathway in autoimmunity was investigated in experimental animal models of disease including T1D, SLE, autoimmune myocarditis, autoimmune encephalomyelitis (EAE), RA, enteropathies as summarized below.
PD-1 polymorphisms and autoimmunity
In humans the association of SNPs in PD-1 gene (PDCD1, located on chromosome 2q37), in particular of PD-1.3, PD-1.5 and PD-1.6, with a higher risk of developing several autoimmune diseases was demonstrated [18], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124]. This confirmed the putative involvement of PDCD1 gene in the regulation of autoimmunity and in the maintenance of tolerance [114], [116], [117], [125], [126], [127].
Nevertheless, no association between PD-1
Conclusive remarks
In the light of the foregoing PD-1 molecule and its ligands clearly represent a pathway with pleiotropic effects on T cell activation, immunological tolerance and immune-mediated tissue damage. They act in many ways by either promoting Treg development/function or inhibiting expansion/activation of effector T cells, thus protecting against autoimmunity. Data obtained from the analysis of experimental models of autoimmunity in addition to the discovery of PD-1 SNPs, found associated with certain
Conflict of interest statement
There is no conflict of interest in the conduction of this study.
Take-home messages
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Genetic and environmental factors underlie the etiopathogenesis of autoimmunity.
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The PD-1/PD-L1 pathway has a role in controlling immunological tolerance.
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PD-1 gene SNPs are associated with several autoimmune conditions in humans.
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Future therapies in autoimmunity may act by modulating the PD1/PD-L1 pathway.
Acknowledgment
This study was supported by the Italian Ministry of Health.
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