Blockade of Programmed Death-1 in Young (New Zealand Black × New Zealand White)F1 Mice Promotes the Activity of Suppressive CD8+ T Cells That Protect from Lupus-Like Disease

Wong, Maurice; Cava, Antonio La; Singh, Ram Pyare; Hahn, Bevra H.

doi:10.4049/jimmunol.0903401

Cited by 39 publications

(27 citation statements)

References 30 publications

(39 reference statements)

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“…This positive effect was difficult to reconcile with the high auto-Ab titers and the lupus symptoms observed in PD-1 knockout mice (21,31). In our study, T regs expressing PD-1 ligands acted negatively on autoreactive PD-1 + B cells, explaining the phenotype of PD-1-deficient mice (21,38). This is no contradiction because T regs will operate only in responses against self-antigens and prevail over the positive effect on follicular Th cells.…”

Section: Discussioncontrasting

confidence: 61%

“…Here we show that T regs control autoreactive B cells specific for tissue auto-Ag through the suppressive surface molecule PD-1. Others have previously shown that follicular Th cells express high amounts of PD-1 (37) and that PD-1 inhibits Th cells (38), suggesting that indirect B-cell suppression, by curbing help for auto-Ab production, may play a role. Cell culture studies by others had hinted at the possibility of direct suppression (10)(11)(12), but providing in vivo evidence required an experimental system by which either the direct or the indirect route of suppression could be incapacitated.…”

Section: Discussionmentioning

confidence: 99%

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Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Gotot¹,

Gottschalk²,

Leopold³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

108

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The mechanisms by which regulatory T cells (T regs ) suppress autoantibody production are unclear. Here we have addressed this question using transgenic mice expressing model antigens in the kidney. We report that T regs were essential and sufficient to suppress autoreactive B cells in an antigen-specific manner and to prevent them from producing autoantibodies. Most of this suppression was mediated through the inhibitory cell-surface-molecule programmed death-1 (PD-1). Suppression required PD-1 expression on autoreactive B cells and expression of the two PD-1 ligands on T regs . PD-1 ligation inhibited activation of autoreactive B cells, suppressed their proliferation, and induced their apoptosis. Intermediate PD-1 + cells, such as T helper cells, were dispensable for suppression. These findings demonstrate in vivo that T regs use PD-1 ligands to directly suppress autoreactive B cells, and they identify a previously undescribed peripheral B-cell tolerance mechanism against tissue autoantigens. Regulatory T cells (T regs ) are powerful suppressors of autoreactive T cells with high therapeutic potential (1-3). T regs also suppress auto-Ab production (4, 5). We recently showed in vivo that they do so in an antigen-specific (Ag-specific) manner (6, 7). These studies used rat insulin promoter HEL/OVA (ROH) mice expressing ovalbumin (OVA) and hen egg lysozyme (HEL) in pancreatic islet β-cells. Autoreactive OVA-and HEL-specific B cells, but not B cells specific for a foreign antigen, failed to proliferate in response to in vivo autoantigen (auto-Ag) challenge and instead underwent apoptosis in a strictly T reg -dependent fashion. T regs can affect B cells indirectly by suppressing the T-helper (Th) cells required for antibody production (8, 9). This did not rule out that T regs might also suppress B cells directly. Cell culture systems have revealed that CD25 + T regs can kill cocultured B cells (10-12). A recent in vivo study showed that T regs enter germinal centers and suppress B cells in this site (13,14). The question whether this occurred directly or indirectly remained open (15). This question is difficult to address in vivo because it requires an experimental system where T regs can suppress B cells but not Th cells.Another open question concerns the molecular mechanisms by which T regs suppress. In principle, T regs may suppress other T cells by (i) secreting inhibitory mediators; (ii) deprivation of survival factors; (iii) killing target cells by granzyme/perforin; and (iv) modulation of DCs by ligating inhibitory T-cell receptors (16,17). The exact contribution of these mechanisms in relevant in vivo situations and the mechanisms by which T regs suppress are unclear.Programmed death-1 (PD-1, CD279) is an activation-induced member of the extended CD28/CTLA-4 family that suppresses T cells (18-21). It has been associated with exhausted memory T cells in chronic viral infection (22,23) and with cytotoxic T-cell cross-tolerance (24). PD-1 has two known ligands, PDL-1 (B7-H1, CD274) and PDL-2 (B7-DC, CD273) (25,...

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Section: Discussioncontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Gotot¹,

Gottschalk²,

Leopold³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

108

View full text Add to dashboard Cite

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“…B7-1 cross-linking activates CD4 + T cells and increases T cell proinflammatory cytokine production (48). Disrupting PD-L1-PD-1 interaction by anti-PD-1 Ab protects lupus-like nephritis in NZB/W F1 mice by either reducing CD4 + PD-1 + T cells (49) or promoting suppressor CD8 + T cell activity (50). However, these anti-PD-1 blocking experiments are long term studies and the results do not necessarily apply to the current short-term anti-GBM model.…”

Section: Discussionmentioning

confidence: 99%

Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow–Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice

Sung

Dai

et al. 2017

The Journal of Immunology

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Glomerular damage mediated by glomerulus-infiltrating myeloid-derived cells is a key pathogenic event in lupus nephritis (LN)c but the process is poorly understood. Confocal microscopy of kidney sections and flow cytometry analysis of glomerular cells from magnetic-bead purified glomeruli have identified glomerulus-infiltrating leukocyte populations in NZM2328 (NZM) lupus-prone mice with spontaneous chronic glomerulonephritis (cGN) and anti-glomerular basement membrane (GBM)-induced nephritis. The occurrence of a major glomerulus-infiltrating CD11b+F4/80−I-A− macrophage population exhibiting the markers PD-L1, Mac-2, and macrophage mannose receptor (MMR, CD206) and producing Klf4, Il10, Retnla, Tnf, and Il6 mRNA which are known to be expressed by alternatively activated (M2b) macrophages correlated with proteinuria status. In NZM mice with spontaneous LN, glomerular macrophage infiltration is predominant. CD11b+F4/80−I-A− intraglomerular macrophages and PMN are important in inducing GN as anti- CD11b and ICAM-1 mAb inhibited both proteinuria and macrophage and PMN infiltration. The predominant and high expression of PD-L1 by CD11b+F4/80−I-A− glomerular macrophages in kidneys of mice with GN and the inhibition of proteinuria by anti-PD-L1 mAb supported the pathogenic role of these macrophages but not the PD-L1− PMN in GN development and in inducing podocyte damage. In NZM mice with spontaneous cGN and severe proteinuria, few glomerulus-infiltrating PMN were found, leaving macrophages and to a lesser extent DC as the major infiltrating leukocytes. These data taken together support the important pathogenic effect of CD11b+F4/80−I-A− M2b-like glomerulus-infiltrating macrophages in LN and reinforce macrophages as a promising target for GN treatment.

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“…Combined with our current results, antibodies against PD-1 might accelerate the severity of lupus in vivo by blocking the biological function of the PD-1 signaling pathway. Controversially, in vivo blockade of PD-1 receptor in a lupus murine model (NZB/WF1) has been shown to delay the disease progression [34–36], and might, owing to the high affinity and doses of commercial PD-1 antibodies administered to mice, result in the dissolution of T cells instead of the inhibition of T cells function.…”

Section: Discussionmentioning

confidence: 99%

Elevated serum autoantibodies against co-inhibitory PD-1 facilitate T cell proliferation and correlate with disease activity in new-onset systemic lupus erythematosus patients

Shi

Teng

et al. 2017

Arthritis Res Ther

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BackgroundProgrammed cell death protein 1 (PD-1) plays an important role in immune response regulation as a co-inhibitory signal during T cell activation. However, there is little known about the serum autoantibody profile of PD-1 in systemic lupus erythematosus (SLE), a disease characterized by the breakdown of immune tolerance to self-antigens and an excessive production of autoantibodies. Thus, we aim to investigate the serum levels and function of anti-PD-1 in patients with new-onset SLE.MethodsSerum levels of anti-PD-1 IgG and IgM isotypes were detected in new-onset SLE patients (n = 90), rheumatoid arthritis (n = 50), primary Sjogren’s syndrome (n = 50), ankylosing spondylitis (n = 25), and healthy controls (HC) (n = 80) using an enzyme-linked immunosorbent assay (ELISA). The correlation of anti-PD-1 with clinical characteristics and laboratory parameters of patients with new-onset SLE was analyzed. The effects of purified anti-PD-1 IgG from SLE patients on T cell proliferation were measured using flow cytometry.ResultsThe data revealed increased levels of anti-PD-1 IgG, but not IgM, especially in new-onset SLE patients, and the positive rate of anti-PD-1 IgG was 30 (33.3%). The level of anti-PD-1 IgG was closely associated with malar rash (OR = 15.773), arthritis (OR = 22.937), serositis (OR = 16.008), hematological (OR = 35.187), renal (OR = 8.306), and neurological involvement (OR = 37.282). Moreover, the serum levels of anti-PD-1 IgG were positively correlated with the SLE disease activity index (SLEDAI) score (r = 0.296, p = 0.0046) and the erythrocyte sedimentation rate (ESR) (r = 0.2446, p = 0.0201). In vitro examination showed that purified anti-PD-1 IgG obtained from SLE patients enhanced T cell proliferation when co-cultured with dendritic cells (DCs).ConclusionsThe current study indicates, for the first time, that the serum levels of co-inhibitor autoantibodies against PD-1 are elevated in new-onset SLE patients and are associated with disease activity in SLE. Autoantibodies against PD-1, facilitating T cell proliferation, revealed a new insight into the function of negative regulation signals involved in the pathogenesis of SLE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1258-4) contains supplementary material, which is available to authorized users.

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Blockade of Programmed Death-1 in Young (New Zealand Black × New Zealand White)F1 Mice Promotes the Activity of Suppressive CD8+ T Cells That Protect from Lupus-Like Disease

Cited by 39 publications

References 30 publications

Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow–Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice

Elevated serum autoantibodies against co-inhibitory PD-1 facilitate T cell proliferation and correlate with disease activity in new-onset systemic lupus erythematosus patients

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