4.1.4 Biological Significance of PD-1/PD-L1 Pathwa...
The non-obese diabetic (NOD) mouse is a spontaneous model of Type 1 diabetes mellitus (T1DM),with genetic and pathophysiological roots comparable with the human disease.PD-1 serves as a protective factor for T1DM.Forced expression of PD-1 in transgenic (Tg) mice, the incidence of autoimmune diabetes was significantly reduced.PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female NOD mice regardless of age.The expression of PD-L1 but not PD-L2 on the islet β-cells may explain the reason why the anti-PD-L1 but not anti-PD-L2 antibody exaggerated diabetes.Whereas, PD-1 or PD-L2, but not PD-L1 blockade accelerated experimental allergic encephalitis (EAE).Since PD-L1 but not PD-L2 was highly expressed in the central nervous system, the expression of ligands in target organs may not determine the efficiency of each blocking antibody.PD-1-/- mice developed lupus-like diseases on the C57BL/6 background,dilated cardiomyopathies on the BALB/c background, while T1DM on NOD background.It indicates that PD-1 deficiency unravels the hidden autoimmune susceptibility of the strain without changing its specificity.It is reported that T1DM is associated with particular HLA/H-2 haplotypes and diabetes-associated H-2g7 can increase the susceptibility to diabetes in a dose dependent fashion.Regarding to the mechanisms of PD-1 in regulation of T1DM, the PD-1/PD-L1 pathway had an effect on TCR-driven stop signal and T-cell motility.Since inhibition of TCR-driven stop signal depended on continued interactions between PD-1 and PD-L1, PD-1 or PD-L1 blockade resulted in lower T-cell motility, enhanced T-DC contacts and caused autoimmune diabetes.CD4+24αβ type II NKT cells, but not CD4/CD8 double-negative NKT cells, provide long-term protection against T1DM by regulating diabetogenic CD4+T cell activation in the pancreatic lymph nodes (PLN), through a mechanism that requires the PD-1/PD-L1 and ICOS/ICOSL pathways [6].
The role of PD-L1 and PD-L2 is more complex than that of PD-1.PD-L1 was previously considered to restrict autoimmune diabetes.PD-L1 deficiency could increase susceptibility to diabetes via a direct effect on pathogenic T cells, while regulatory T cells (Tregs) and B cells prevented autoimmune diabetes via a mechanism independent of PD-1/PD-L1 pathway.However,recent studies showed that co-stimulatory or co-inhibitory signals provided by PD-Ls may depend upon the timing and locale, the type of immune cells involved, relative levels of PD-1 and non-PD-1 molecules on T cells.Regulation mediated by PD-Ls is dependent upon events occurring in the PLN during early disease stages, but becomes independent of PLN during later disease stages.PD-L1 and PD-L2 on APCs may have overlapping functions to provide positive signals to naive auto-reactive T cells in the PLN, possibly via a non-PD-1 receptor.After migration into pancreatic islets, activated effector T cells and other immune cells release inflammatory cytokines such as IFN-γ that upregulates PD-L1 on islets.The unique expression of PD-L1 instead of PD-L2 in the pancreatic islets leads to its predominant role in inhibiting β-cell destruction mediated by pathogenic T cells [6].
In additional, even tissue specific expression of PD-L1 can have distinct outcomes depending on the genetic strain.For example, PD-L1 overexpression on islets promotes diabetes on the C57BL/6 background, but NOD mice are protected from diabetes by islet PD-L1 overexpression.It is difficult to reconcile these findings.But at the very least, one must conclude that genetic background is important for the function of the PD-1/PD-Ls pathway.Moreover, PD-L1 has two known binding partners, PD-1 and B7-1.However, unlike PD-L1/PD-1 pathway, the PD-L1/B7-1 pathway has no effect on TCR-driven stop signal and T-cell motility.The PD-L1/B7-1 pathway can restrain the responses of pathogenic effector CD4+ and CD8+T cells and this inhibition may be particularly important during the later phases of diabetogenesis [1].
Diabetogenic T cells are generated in the context of genetic strain.The PD-1/PD-L1 pathway deficiency caused by genetic and/or environmental factors unravels the hidden autoimmune susceptibility of the strain.After migration from thymus to the pancreatic lymph nodes (PLN),PD-L1 and PD-L2 on antigen-presenting cells (APCs) provide positive signals to diabetogenic T cells, possibly via a non-PD-1 receptor and provide negative signals via PD-1.Moreover, CD4+Type II NKT cells can restrain the diabetogenic T cellactivation.It may prevent T cell activation by directly interacting with these cells and/or negatively regulating APCs [1].
Although the co-existence of positive and negative signals, negative signals predominate as a whole.Because PD-1 or PD-L1 blockade rapidly precipitates, not prevents diabetes in neonates of NOD mice.After migration into pancreatic islets, activated effector T cells and other immune cells release inflammatory cytokines such as IFN-γ that upregulates PD-L1 on islets.The unique expression of PD-L1 instead of PD-L2 in the pancreatic islets leads to its predominant role in inhibiting β-cell destruction mediated by pathogenic effector T cells.In additional, the PD-L1/B7-1 pathway can restrain the effector T cell responses and the inhibition may be particularly important during the later phases of diabetogenesis [1].(https://www.daowen.com)
Since genetic background is a key factor for PD-1/PD-Ls signal, it becomes more important to elucidate the role in human specially.However, aside from researches on genetic polymorphism,there has been only one group exploring the role in T1DM patients and a significantly decreased expression of PD-1 was observed on peripheral CD4+T cells [1].
(New Zealand Black × New Zealand White) F1 (BWF1) mice spontaneously develop a syndrome resembling human systemic lupus erythematosus (SLE) and are frequently used as surrogates for studying this disease.The PD-1/PD-Ls pathway plays important roles in SLE, as evidenced by the lupus like glomerulonephritis developed by PD-1 knockout mice on the C57BL/6 background.By contrast, anti-PD-1-treated premorbid BWF1 mice were protected from lupus nephritis.Further studies showed that anti-PD-1 mAb preserved the number of suppressive CD8+Foxp3+T cells that suppressed both CD4+Th cells and B cells.Although the PD-1 expression on CD8+Foxp3+T cells is decreased by anti-PD-1 mAb, PD-1 is still present.Intriguingly, silencing PD-1 with small interfering RNA in these adaptive CD8+Foxp3+T cells abrogated their suppressive capacities.It suggests that PD-1 expression has to be tuned finely, neither absent nor high, to enable CD8+Foxp3+T cells to control autoimmunity, which may account for the opposite results between PD-1 knockout and PD-1 blockade.Meanwhile, the curative effects of anti-PD-1 and anti-PD-L1 mAb in BWF1 mice are examined and found that anti-PD-1 mAb reduced mortality rate significantly by reducing CD4+PD-1+T cells and the production of IFN-γ and IgG2a anti-ds-DNA Abs.Conversely, anti-PD-L1 mAb had a quite opposing effect.Contrary to the curative effects just mentioned, injection of anti-PD-1 mAb exacerbated EAE and NOD diabetes.One explanation is that BWF1 mice show the property of a disease mediated by immunecomplex, whereas neither NOD nor EAE mice do.Another explanation is that the nephritis of BWF1 mice develops more chronically and the effector/memory CD4+PD-1+T cells are relatively resistant to the PD-1/PD-Ls inhibition.However, CD4+PD-1+T cells in NOD/EAE mice may be newly arising and more susceptible to the inhibition.Studies show that lupic DCs and CD4+T cells are characterized by overexpression of PD-Ls and PD-1, respectively.It is interesting that CD4+PD-1highT cells are high IFN-γ producers when we consider the features of CD8+PD-1highT cells in chronic viral infections, which have been defined as “exhausted T cells”.It is necessary to dissect the molecular mechanisms underlying the dysregulation of PD-1 signaling in CD4+PD-1highT cells [1].
Collagen II (CII)-induced arthritis (CIA) is a murine model extensively used to elucidate the rheumatoid arthritis (RA) pathogenesis and discover new therapeutics.The PD-1/PD-L1 pathway is considered to serve as a protective factor for RA.PD-1-/- mice increased incidence and severity of CIA and this effect was associated with enhanced T-cell proliferation and increased production of cytokines (IFN-γ and IL-17), whereas production of IL-10 and anti-CII IgG was not affected.Thus PD-1 regulates the Th1/Th17 pathway rather than the Th2 or humoral responses.Similarly,PD-L1-/-mice exacerbated proteoglycan (PG)-induced arthritis(PGIA) and enhanced Th1 CD4+T cell responses.Mechanistically, PD-L1 on non-B and non-T cells was sufficient to prevent the development of PGIA.Unexpectedly, the PG-specific antibody response in PD-L1-/- mice was diminished.Thus a novel role for PD-L1 expression on non-B and non-T cells was discovered, that is, they can promote B-cell survival and maintain autoantibody responses by preventing hyperactive T follicular helper (Tfh) cell-induced germinal center (GC) B cell apoptosis.Consistently, the PD-1/PD-Ls pathway can regulate GC B cell survival, as well as the formation and affinity of long-lived plasma cells.The diminished PG-specific antibody responses in PD-L1-/-mice and the unchanged anti-CII IgG in PD-1-/- mice seem in conflict.Together, it is hardly to determine the role of PD-1/PD-L1 pathway in regulating B cell responses in murine model of RA.But at the very least, one must conclude that the PD-1/PD-L1 signal involved in humoral responses is not the key pathological mechanism for RA.Despite reduced autoantibodies, PD-L1-/-mice do develop sufficient autoantibodies to induce PGIA.The mechanism may be more influential in other diseases mediated by antibodies.For example, in a model of autoimmune nephritis PD-L1-/- mice do not experience an increased incidence or severity of glomerular IgG deposits.In addition, the effects of PD-L1-Ig on CIA were investigated and mice with PD-L1-Ig treatment antagonized the CIA development as assessed by clinical arthritis score and joint histology [1].
Taken together, PD-1 maintains tolerance by mechanisms fundamentally distinct from those of CTLA-4.Firstly, CTLA-4 deficiency results in rapid multi-organ tissue inflammation and death regardless of mouse genetic background.Conversely, PD-1 deficiency causes tissue specific injury slowly, in a manner depending on genetic background.Secondly, CTLA-4/B7 blockade enhances the antitumor immune responses concomitant with the formation of autoimmune responses, but that is not the case for the blockade of PD-1/PD-Ls pathway.Thirdly, in NOD murine model, CTLA-4 blockade induces diabetes only in neonates.By contrast, PD-1 or PD-L1 blockade rapidly precipitates diabetes regardless of age.Fourthly, PD-1 or PD-L1 blockade results in lower T-cell motility [7, 8].