Regulation of T-Cell Chemotaxis by Programmed Death-Ligand 1 (PD-L1) in Dry Eye–Associated Corneal Inflammation

Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell– but not B cell–dependent because PDL1-specific antibody treatment caused fetal rejection in B cell–deficient but not in RAG-1–deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-γ–producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-γ levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.

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Prognostic value of programmed death-1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma

Chinese Journal of Cancer ◽

10.1186/s40880-017-0226-3 ◽

2017 ◽

Vol 36 (1) ◽

Cited By ~ 20

Author(s):

Yuan Gao ◽

Su Li ◽

Dazhi Xu ◽

Shangxiang Chen ◽

Yuchen Cai ◽

...

Keyword(s):

T Cell ◽

Lymph Nodes ◽

Cell Density ◽

Prognostic Value ◽

Cd8 T Cell ◽

Primary Tumors ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Programmed Death 1 ◽

Stage T1

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Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1- and prostaglandin E2-induced regulatory T cell expansion

Scientific Reports ◽

10.1038/srep24193 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 29

Author(s):

Sahana Holla ◽

Emmanuel Stephen-Victor ◽

Praveen Prakhar ◽

Meenu Sharma ◽

Chaitrali Saha ◽

...

Keyword(s):

T Cell ◽

Prostaglandin E2 ◽

Sonic Hedgehog ◽

Regulatory T Cell ◽

Cell Expansion ◽

Hedgehog Signaling ◽

Sonic Hedgehog Signaling ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

T Cell Expansion

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Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Cancers ◽

10.3390/cancers12010057 ◽

2019 ◽

Vol 12 (1) ◽

pp. 57

Author(s):

Man-Chin Chen ◽

Christian Ronquillo Pangilinan ◽

Che-Hsin Lee

Keyword(s):

T Cell ◽

Tumor Growth ◽

Tumor Cells ◽

Immune Checkpoint ◽

Immune Escape ◽

Cell Infiltration ◽

Tumor Immune Escape ◽

Programmed Death Ligand 1 ◽

T Cell Infiltration ◽

Programmed Death

Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

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Antigen-Specific Transfer of Functional Programmed Death Ligand 1 From Antigen Presenting Cells Onto Human CD8+ T Cells Via Trogocytosis

Blood ◽

10.1182/blood.v116.21.584.584 ◽

2010 ◽

Vol 116 (21) ◽

pp. 584-584

Author(s):

Regina Gary ◽

Simon Voelkl ◽

Ralf Palmisano ◽

Andreas Mackensen

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

T Cell Responses ◽

Antigen Presenting Cells ◽

Programmed Death Ligand 1 ◽

Cell Responses ◽

Surface Molecules ◽

Programmed Death ◽

Antigen Presenting

Abstract Abstract 584 Specific T-cell responses are initiated by T-cell receptor (TCR) recognition of peptide-MHC-complexes on antigen presenting cells (APCs). Upon specific interaction of T cells with APCs T cells capture membrane fragments and surface molecules of APCs in a process termed trogocytosis. Exchange of membrane molecules/antigens between immune cells has been observed for a long time, but the mechanisms and functional consequences of these transfers remain unclear. Here, we demonstrate that human antigen-specific CD8+ T cells do acquire the co-inhibitory molecule programmed death ligand 1 (PD-L1) from mature monocyte-derived dendritic cells (mDC) and tumor cells in an antigen-specific manner. The kinetics of PD-L1 transfer revealed a maximal PD-L1 expression on antigen-specific T cells within 3–4 hours after co-incubation with antigen-pulsed APCs, being detectable up to 72 hours. Antigen-pulsed immature DCs were less effective in transfering surface molecules such as PD-L1 onto CD8+ T cells after antigen-specific recognition. Using a transwell system we could show that the acquisition of PD-L1 requires cell-cell contact. Furthermore, PD-L1 cannot be acquired by T cells from a lysate of mDCs. The transfer process is impaired after pretreatment of T cells with concanamycin A, a specific inhibitor of vacuolar ATPases, playing an important role in membrane trafficking. Moreover, fixation of DCs with glutaraldehyde completely abrogated the acquisition of PD-L1 on T cells suggesting that an active interaction between APCs and T cells is required for trogocytosis. Of importance, CD8+ T cells which acquired PD-L1 complexes, were able to induce apoptosis of neighbouring PD-1 expressing CD8+ T cells, that could be completely blocked by an anti-PD-L1 antibody. In summary our data demonstrate for the first time that human antigen-specific CD8+ T cells take up functionally active PD-L1 from APCs in an antigen-specific fashion, leading to apoptosis of PD-1 expressing T cells. The transfer of functionally active co-inhibitory molecules from APCs onto human CD8+ T cells may serve to limit clonal expansion of antigen-specific T-cell responses but may also play a major role for T-cell exhaustion in chronic infection and tumor immunosurveillance. Disclosures: No relevant conflicts of interest to declare.

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