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References 4 and 5 present the first descriptions of PDL2 as a second ligand for PD1. Reference 4 also provides one of the first descriptions of PDL1 and PDL2 expression by tumour cells.
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This study describes the development of the first Pdcd1-knockout mouse. Characterization of Pdcd1-knockout in the C57BL/6 background shows genetic loss of potentiated autoimmunity, as these mice developed a lupus-like disease.
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This study provides the first description of high and sustained expression of PD1 on exhausted T cells in chronic infection. The authors show that administering blocking antibodies against the PD1 pathway after the onset of exhaustion partially reverses this dysfunctional state. However, loss of PD1 signalling early (in Cd274-knockout mice) results in lethal immunopathology.
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One of the first descriptions of loss of PD1 signalling promoting immunity to cancer in mice. Using both overexpression of PDL1 and blocking antibodies against PDL1, the authors show that perturbing the PD1 pathway can influence tumour growth in mice.
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This is a key paper showing synergy with combination therapy (using PD1 and CTLA4 inhibitors) for the treatment of metastatic melanoma in patients. Compared with monotherapy targeting PD1 or CTLA4, combination therapy shows greater efficacy but also higher rates of adverse events.
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This study presents a key comparison of PD1 and CTLA4 signalling, showing that these pathways are not redundant. Both PD1 and CTLA4 signalling can target the AKT pathway, although CTLA4 does so through PP2A regulating AKT, whereas PD1 targets the AKT pathway by inhibiting CD28-mediated activation of PI3K. The authors also show the importance of the immunoreceptor tyrosine-based switch motif of PD1 in mediating signalling.
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This key report shows the unique biological roles for PDL1 in haematopoietic versus non-haematopoietic cells during chronic infection. PDL1 on haematopoietic cells limits CD8+ T cell functions, whereas PDL1 on non-haematopoietic cells regulates viral replication and immunopathology.
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One of the first studies to describe the tissue expression (both haematopoietic and non-haematopoietic) of PDL1 and PDL2.
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This is a key paper showing potent synergy of combination therapy (targeting PD1 and LAG3) in mouse models of cancer. The authors show that loss of both PD1 and LAG3 has better antitumour efficacy than loss of either inhibitory receptor alone.
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