PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells

Latchman, Yvette; Liang, Spencer; Wu, Yin; Chernova, Tatyana; Sobel, Raymond A.; Klemm, Martina; Kuchroo, Vijay K.; Freeman, Gordon J.; Sharpe, Arlene H.

doi:10.1073/pnas.0307252101

Cited by 557 publications

(518 citation statements)

References 30 publications

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“…PD-1-knockout mice spontaneously develop phenotypes of lymphoproliferative autoimmune diseases, accompanied by a marked accumulation of inflammatory cells in affected organs, including CD4+ and CD8+ T cell subsets [37]. Autoimmune manifestations in PD-1 mice are different from those observed in CTLA-4 −/− mice, which die at 3-4 weeks of age from massive lymphocytic infiltration and tissue destruction in multiple organs [38].…”

Section: Pd-1/pd-l1 Expression and Biological Functionmentioning

confidence: 99%

Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities

Merelli

Massi

Cattaneo

et al. 2014

Critical Reviews in Oncology/Hematology

150

106

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Section: Pd-1/pd-l1 Expression and Biological Functionmentioning

confidence: 99%

Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities

Merelli

Massi

Cattaneo

et al. 2014

Critical Reviews in Oncology/Hematology

150

106

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“…Depending on the model system, PD-L1 and PD-L2 were initially reported to have inhibitory or stimulatory effects on T cell responses (13,14). 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).…”

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

Self Cite

214

169

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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 -/-mice PD-L1 -/-mice were generated as described [15]. To generate PD-L2 -/-mice, a targeting vector was designed to replace the IgV exon of the PD-L2 gene with the hygromycin drug resistance gene (Fig.…”

Section: Micementioning

confidence: 99%

“…Initial reports suggested that PD-L1 and PD-L2 inhibit T cell proliferation and cytokine production, while others suggested that these molecules are costimulatory, enhancing proliferation and effector functions. The phenotype of PD-L1 -/-mice [15] demonstrates that PD-L1 has a critical negative regulatory role in vivo. PD-L1 inhibits CD4 + and CD8 + IFN-c production in vivo.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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To compare the roles of programmed death 1 ligand 1 (PD‐L1) and PD‐L2 in regulating immunity to infection, we investigated responses of mice lacking PD‐L1 or PD‐L2 to infection with Leishmania mexicana. PD‐L1–/– and PD‐L2–/– mice exhibited distinct disease outcomes following infection with L. mexicana. In comparison to susceptible WT mice, PD‐L1–/– mice showed resistance to L. mexicana, as demonstrated by reduced growth of cutaneous lesions and parasite burden. In contrast, PD‐L2–/– mice developed exacerbated disease with increased parasite burden. Host resistance to L. mexicana is partly associated with the development of a Th1 response and down‐regulation of the Th2 response. Both PD‐L1–/– and PD‐L2–/– mice produced levels of IFN‐γ similar to WT mice. However, the development of IL‐4‐producing cells was reduced in PD‐L1–/– mice, demonstrating a role for PD‐L1 in regulating Th cell differentiation. This inadequate Th2 response may explain the increased resistance of PD‐L1–/– mice. Although no alterations in Th1/Th2 skewing were observed in PD‐L2–/– mice, PD‐L2–/– mice exhibited a marked increase in L. mexicana‐specific antibody production. Increased Leishmania‐specific IgG production may suppress the healing response through FcγR ligation on macrophages. Taken together, our results demonstrate that PD‐L1 and PD‐L2 have distinct roles in regulating the immune response to L. mexicana.

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PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells

Cited by 557 publications

References 30 publications

Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities

Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities

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

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

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