Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors

Wang, Shufang; Fouquet, Stéphane; Chapon, Maxime; Salmon, Hélène; Régnier, Fabienne; Labroquère, Karine; Badoual, Cécile; Damotte, Diane; Validire, Pierre; Maubec, Ève; Delongchamps, Nicolas Barry; Cazes, Aurélie; Gibault, Laure; Garcette, Marylène; Dieu-Nosjean, Marie-Caroline; Zerbib, Marc; Avril, Marie-Françoise; Prévost-Blondel, Armelle; Randriamampita, Clotilde; Trautmann, Alain; Bercovici, Nadège

doi:10.1371/journal.pone.0017621

Cited by 80 publications

(81 citation statements)

References 33 publications

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“…In the presence of PD-L1 expression on aAPCs, we observed a clear inverse correlation between the level of PD-1 expression and the number of T cells fluxing Ca . These studies are consistent with the notion that PD-1 ligation can interfere with the most membrane-proximal signaling events (32) and clearly demonstrate that the ability of PD-L1-expressing aAPCs to inhibit Ca 2+ is directly proportional to the amount of PD-1 on the T-cell surface.…”

Section: Pd-1 Inhibits Casupporting

confidence: 88%

Strength of PD-1 signaling differentially affects T-cell effector functions

Wei

Shi

et al. 2013

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

246

184

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High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca 2+ flux, we found that PD-1 ligation dramatically shifts the dose-response curve, making T cells much less sensitive to T-cell receptor-generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.

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Section: Pd-1 Inhibits Casupporting

confidence: 88%

Strength of PD-1 signaling differentially affects T-cell effector functions

Wei

Shi

et al. 2013

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

246

184

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“…Three weeks after induction of complete chimerism, we checked the residual host-type T cells regarding surface marker changes related to T cell anergy such as upregulation of PD-1 and downregulation of IL-7Ra (27)(28)(29), surface marker changes related to apoptosis such as upregulation of FAS (34), and surface marker changes related to T cell exhaustion such as upregulation of TIM-3 (35,36). We found that, although there was no significant difference between host-type T cells from recipients given TCD-BM from MHC II 2/2 mismatched or MHC-matched donors, the host-type T cells from recipients given TCD-BM from MHC-mismatched WT donors upregulated PD-1 expression (p , 0.01; Fig.…”

Section: Mhc-mismatched Complete Chimerism Induces Tolerance Of Pre-ementioning

confidence: 99%

“…The residual host-type T cells in the MHC-mismatched complete chimeras appeared to be anergic with upregulation of PD-1 and downregulation of IL-7Ra. Anergic T cells were reported to upregulate PD-1 and downregulate IL-7Ra (27)(28)(29).…”

mentioning

confidence: 99%

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Wang

Racine

Zhang

et al. 2014

The Journal of Immunology

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In nonautoimmune recipients, induction of mixed and complete chimerism with hematopoietic progenitor cells from MHC (HLA)-matched or -mismatched donors are effective approaches for induction of organ transplantation immune tolerance in both animal models and patients. But it is still unclear whether this is the case in autoimmune recipients. With the autoimmune diabetic NOD mouse model, we report that, although mixed and complete MHC-mismatched chimerism provide immune tolerance to donor-type islet and skin transplants, neither mixed nor complete MHC-matched chimerism does. The MHC-mismatched chimerism not only tolerizes the de novo developed, but also the residual pre-existing host-type T cells in a mismatched MHC class II–dependent manner. In the MHC-mismatched chimeras, the residual host-type peripheral T cells appear to be anergic with upregulation of PD-1 and downregulation of IL-7Rα. Conversely, in the MHC-matched chimeras, the residual host-type peripheral T cells manifest both alloreactivity and autoreactivity; they not only mediate insulitis and sialitis in the recipient, but also reject allogeneic donor-type islet and skin grafts. Interestingly, transgenic autoreactive BDC2.5 T cells from Rag1+/+, but not from Rag1−/−, NOD mice show alloreactivity and mediate both insulitis and rejection of allografts. Taken together, MHC-mismatched, but not MHC-matched, chimerism can effectively provide transplantation immune tolerance in autoimmune recipients.

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“…B7-H1 molecules expressed on tumor cells play a crucial role in tumor evasion from cytotoxic T lymphocyte (CTL)-mediated immune surveillance through PD-1 (9,10). Tumor-associated B7-H1 delivers an inhibitory signal to tumor-specific CTLs via the B7-H1-PD-1 interaction, resulting in T-cell apoptosis in vitro and in vivo, and the B7-H1-PD-1 interaction attenuates activated tumor-infiltrating T cells through the inhibition of T-cell receptor (TCR) signaling (1,4,11,12). We previously demonstrated that B7-H1-positive myelodysplastic syndrome blasts have a greater ability to induce T-cell apoptosis compared with B7-H1-negative blasts, through the B7-H1-PD-1 pathway (3).…”

Section: Introductionmentioning

confidence: 99%

Myeloma Drug Resistance Induced by Binding of Myeloma B7-H1 (PD-L1) to PD-1

Ishibashi

Tamura

Sunakawa

et al. 2016

Cancer Immunology Research

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B7 homolog 1 (B7-H1)-expressing myeloma cells not only inhibit myeloma-specific cytotoxic T lymphocytes (CTL), but also confer a proliferative advantage: resistance to antimyeloma chemotherapy. However, it remains unknown whether B7-H1 expressed on myeloma cells induces cellular responses associated with aggressive myeloma behaviors. To address this question, we analyzed the proliferation and drug sensitivity of B7-H1-expressing myeloma cells transfected with B7-H1-specific short-hairpin RNA or treated with programmed cell death (PD)-1-Fc-coupled beads. Knockdown of B7-H1 expression in myeloma cells significantly inhibited cell proliferation and increased apoptosis induced by the chemotherapeutic alkylating agent melphalan, with downregulation of the expression of cell cycle-related genes (CCND3 and CDK6) and antiapoptotic genes (BCL2 and MCL1). B7-H1 molecules thus contributed to myeloma cell-cycle progression and suppression of drug-induced apoptosis. B7-H1-expressing myeloma cells had a higher affinity for PD-1 than for CD80. PD-1-Fc beadtreated myeloma cells also became resistant to apoptosis that was induced by melphalan and the proteasome inhibitor bortezomib. Apoptosis resistance was associated with the PI3K/AKT pathway. Both myeloma cell drug resistance and antiapoptotic responses occurred through the PI3K/AKT signaling pathway, initiated from "reverse" stimulation of B7-H1 by PD-1. Therefore, B7-H1 itself may function as an oncogenic protein in myeloma cells. The interaction between B7-H1 on myeloma cells and PD-1 molecules not only inhibits tumorspecific CTLs but also induces drug resistance in myeloma cells through the PI3K/AKT signaling pathway. These observations provide mechanistic insights into potential immunotherapeutic benefits of blocking the B7-H1-PD-1 pathway.

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Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors

Cited by 80 publications

References 33 publications

Strength of PD-1 signaling differentially affects T-cell effector functions

Strength of PD-1 signaling differentially affects T-cell effector functions

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Myeloma Drug Resistance Induced by Binding of Myeloma B7-H1 (PD-L1) to PD-1

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