PD‐L1 and PD‐L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis

Liang, Spencer; Greenwald, Rebecca J.; Latchman, Yvette; Rosas, Lucia E.; Satoskar, Abhay R.; Freeman, Gordon J.; Sharpe, Arlene H.

doi:10.1002/eji.200535458

Cited by 76 publications

(73 citation statements)

References 25 publications

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“…Without inflammatory challenges, PD-L1/2 -/-mice do not show overt manifestations of dysregulated immunity for many months. However, in the setting of infections, allografts, or preexisting susceptibility to autoimmunity, the absence or blockade of PD-L1, PD-L2, or PD-1 result in enhanced T cell responses and disease (18,(27)(28)(29)(30). Our results indicate that hypercholesterolemia and the resulting arterial pathology represent another systemic immune challenge that is regulated by the PD-L1/2 pathway.…”

Section: Discussionmentioning

confidence: 74%

“…Our finding that CD8 + T cell infiltration in atherosclerotic lesions was markedly enhanced in PD-L1/2-deficient mice is of interest, because CD8 + T cells are usually scarce in lesions compared with CD4 + T cells (1). Recent studies have shown that PD-1 is upregulated on CD8 + T cells in the setting of chronic viral infections, leading to an "exhausted" phenotype characterized by functional impairment of the T cells (28,(38)(39)(40). Blockade of PD-1 can reverse this exhausted phenotype (38,39).…”

Section: Discussionmentioning

confidence: 78%

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Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice

Gotsman

Grabie²,

DaCosta³

et al. 2007

J. Clin. Invest.

177

152

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 78%

Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice

Gotsman

Grabie²,

DaCosta³

et al. 2007

J. Clin. Invest.

177

152

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“…PDL1 and PDL2 thus appear to be similar to the other binary costimulatory systems, such as CD80͞CD86 (4) and CD28͞inducible costimulator (38). In addition to their overlapping function, PDL1 and PDL2 were reported to play distinct roles in immune responses to Leishmaniasis mexicana (39). Compared with the WT mice, PDL1Ϫ͞Ϫ mice showed resistance to L. mexicana infection with a reduced IL-4 producing cell development, whereas PDL2Ϫ͞Ϫ mice exhibited increased susceptibility to the infection with enhanced T-dependent and T-independent humoral immune responses.…”

Section: Discussionmentioning

confidence: 78%

Regulation of T cell activation and tolerance by PDL2

Zhang

Chung

Bishop

et al. 2006

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

141

128

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T cell activation and tolerance are regulated by costimulatory molecules. Although PD-1 serves as a crucial negative regulator of T cells, the function of its ligands, PDL1 and PDL2, is still controversial. In this study, we created a PDL2-deficient mouse to characterize its function in T cell activation and tolerance. Antigenpresenting cells from PDL2؊͞؊ mice were found to be more potent in activation of T cells in vitro over the wild-type controls, which depended on PD-1. Upon immunization with chicken ovalbumin, PDL2؊͞؊ mice exhibited increased activation of CD4 ؉ and CD8 ؉ T cells in vivo when compared with WT animals. In addition, T cell tolerance to an oral antigen was abrogated by the lack of PDL2. Our results thus demonstrate that PDL2 negatively regulates T cells in immune responses and plays an essential role in immune tolerance.costimulation ͉ cytokines ͉ PD-1 D uring infection, pathogen-specific T cells are activated, undergo robust clonal expansion, and subsequently differentiate into effector cells. In contrast, peripheral tolerance mechanisms have been found to prevent autoreactive T cell function (1, 2). Oral tolerance is a form of peripheral tolerance, in which antigen-specific T cell tolerance is induced against oral antigens (3). Although oral tolerance has been tested for protection against autoimmune and allergic diseases, the cellular and molecular mechanisms underlying oral tolerance induction have remained unclear.T cell activation and tolerance are critically regulated by costimulatory molecules, especially those in the B7 and CD28 superfamilies (4). PD-1, a novel member of the CD28 family, is expressed on activated T cells and B cells (5). PD-1 has been shown to be a negative regulator of T cell activation and is crucial for maintaining immune tolerance. PD-1 deficiency in mouse results in spontaneous autoimmune diseases (6, 7). Moreover, PD-1 deficiency (8) or blockade (9) accelerated autoimmune diabetes on NOD background. Blocking PD-1 also enhanced experimental autoimmune encephalomyelitis (EAE) disease (10).Two ligands, B7-H1͞PDL1 and PDL2͞B7DC, have been found to bind to . The function of PDL1 and PDL2 in T cell activation is still in debate. Contradictory results have suggested PDL2 serves as a negative and a positive regulator of T cell function. Latchman et al. (13) have shown that recombinant PDL2 protein inhibited the activation and cytokine production of CD4 ϩ T cells via cell-cycle arrest, whereas Tseng et al. (14) published that B7DC-Ig costimulated the proliferation of naïve T cells at suboptimal anti-CD3 concentrations, and that it increased IFN-␥ secretion. Others studied PDL2 function by using antibodies that block PDL2 binding to PD-1. Salama et al. (10) reported exacerbation of EAE disease when PDL2, but not PDL1, was blocked. In a model of airway hypersensitivity, Matsumoto et al. (15) found that anti-PDL2 antibody administered at the time of challenge increased eosinophilia. These data suggest that PDL2, through engaging PD-1, negatively regulates T cell priming...

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“…Recent reports on PD-L1 using knockout mice or in vivo studies with blocking anti-PD-L1 mAbs have been consistent with an inhibitory role for PD-L1 (13,16,(21)(22)(23)(24)(25)(26). Recent reports on PD-L2 using knockout mice or blocking mAbs still find opposing functions (27,28). The basis for these conflicting results…”

Section: Pd-1:pd-l1 Interactionsmentioning

confidence: 99%

PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver

Maier

Isogawa

Freeman

et al. 2007

The Journal of Immunology

214

172

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Mechanisms contributing to the development of chronic viral infections, including chronic hepatitis B virus (HBV) infections, are not well understood. We have shown recently that production of IFN-γ, an important antiviral cytokine, by HBV-specific CTLs is rapidly induced when they enter the liver of HBV transgenic mice, and then rapidly suppressed, despite the continued presence of Ag. Suppression of IFN-γ production by the CTLs coincides with the up-regulation of programmed cell death (PD)-1, a cell surface signaling molecule known to inhibit T cell function. To determine whether PD-1 plays a role in the functional suppression of IFN-γ secretion by CTLs, we treated HBV transgenic mice with blocking Abs specific for PD ligand (PD-L)1, the most widely expressed PD-1 ligand, and adoptively transferred HBV-specific CTLs. Treatment with anti-PD-L1 Abs resulted in a delay in the suppression of IFN-γ-producing CTLs and a concomitant increase in the absolute number of IFN-γ-producing CTLs in the liver. These results indicate that PD-1:PD-L1 interactions contribute to the suppression of IFN-γ secretion observed following Ag recognition in the liver. Blockade of inhibitory pathways such as PD-1:PD-L1 may reverse viral persistence and chronic infection in cases in which the CTL response is suppressed by this mechanism.

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PD‐L1 and PD‐L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis

Cited by 76 publications

References 25 publications

Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice

Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice

Regulation of T cell activation and tolerance by PDL2

PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver

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