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Results for “Programmed Cell Death 1 Receptor”

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PubMed2003

Cooperative B7-1/2 (CD80/CD86) and B7-DC costimulation of CD4+ T cells independent of the PD-1 receptor.

B7-DC is a recently discovered member of the B7 family that binds to PD-1 and is selectively expressed by dendritic cells (DCs). It has been shown to either costimulate or inhibit T cell responses. To assess the role of B7-DC in DC-T cell interactions, DCs from B7-DC knockout (KO) mice were generated and compared with DCs from wild-type (WT) and B7-1/B7-2 double KO mice. B7-1/B7-2-deficient DCs, while strongly diminished in their ability to stimulate naive CD4+ T cells, nonetheless retain partial activity. DCs from B7-DC KO mice are diminished in their ability to activate CD4+ T cells, demonstrating that DC-expressed B7-DC serves a predominantly stimulatory rather than inhibitory function in the initiation of T cell responses. B7-DC costimulates expression of CD40L with faster kinetics than B7-1 and displays potent synergy with B7-1 and B7-2 for T cell proliferation and cytokine production, indicating that these B7 family members work in concert to stimulate T cells. Finally, costimulation with B7-DC alone or in conjunction with B7-1 is PD-1 independent, indicating that B7-DC costimulates T cells via a second receptor.

Animals↗

PubMed2003

Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction.

B7-H1 and B7-DC are ligands for PD-1, a receptor implicated in negative regulation of T and B cell functions. These ligands, however, also costimulate T cell responses. It remains elusive whether or not costimulation is mediated through PD-1. By comparative molecular modeling and site-directed mutagenesis, we found that nonconserved residues between these ligands on the A'GFCC'C" face mediate interaction with PD-1. This indicates significant structural heterogeneity of the interactions between PD-1 and its ligands. Importantly, ligand mutants with abolished PD-1 binding capacity could still costimulate proliferation and cytokine production of T cells from normal and PD-1-deficient mice. Our results reveal unique binding characteristics of B7-H1 and B7-DC and provide direct evidence for an independent costimulatory receptor other than PD-1.

Amino Acid Sequence↗

PubMed2006

Cutting edge: B and T lymphocyte attenuator and programmed death receptor-1 inhibitory receptors are required for termination of acute allergic airway inflammation.

T cell activation is regulated by coordinate interaction of the T cell Ag receptor and costimulatory signals. Although there is considerable insight into processes that regulate the initiation of inflammation, less is known about the signals that terminate immune responses. We have examined the role of the inhibitory receptors programmed death receptor-1 and B and T lymphocyte attenuator in the regulation of allergic airway inflammation. Our results demonstrate that there is a temporally regulated expression of both the receptors and their ligands during the course of allergic airway inflammation. Following a single inhaled challenge, sensitized wild-type mice exhibit peak inflammation on day 3, which resolves by day 10. In contrast, mice deficient in the expression of programmed death receptor-1 or B and T lymphocyte attenuator have persistent inflammation out to 15 days following challenge. Thus, these receptors are critical determinants of the duration of allergic airway inflammation.

Acute Disease↗

PubMed2001

PD-1: an inhibitory immunoreceptor involved in peripheral tolerance.

PD-1 deficiency causes a variety of autoimmune diseases. Inhibitory signaling through the PD-1 receptor might therefore be involved in the regulation of peripheral tolerance. The constitutive expression of PD-1 ligands (PD-L1 and PD-L2) on parenchymal cells of heart, lung and kidney suggests that the PD-1-PD-L system could provide unique negative signaling to help prevent autoimmune diseases.

Animals↗

PubMed1996

Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes.

A mAb J43 has been produced against the product of the mouse PD-1 gene, a member of the Ig gene superfamily, which was previously isolated from an apoptosis-induced T cell hybridoma (2B4.11) by using subtractive hybridization. Analyses by flow cytometry and immunoprecipitation using the J43 mAb revealed that the PD-1 gene product is a 50-55 kDa membrane protein expressed on the cell surface of several PD-1 cDNA transfectants and 2B4.11 cells. Since the molecular weight calculated from the amino acid sequence is 29, 310, the PD-1 protein appears to be heavily glycosylated. Normal murine lymphoid tissues such as thymus, spleen, lymph node and bone marrow contained very small numbers of PD-1(+) cells. However, a significant PD-1(+) population appeared in the thymocytes as well as T cells in spleen and lymph nodes by the in vivo anti-CD3 mAb treatment. Furthermore, the PD-1 antigen expression was strongly induced in distinct subsets of thymocytes and spleen T cells by in vitro stimulation with either anti-CD3 mAb or concanavalin A (Con A) which could lead T cells to both activation and cell death. Similarly, PD-1 expression was induced on spleen B cells by in vitro stimulation with anti-IgM antibody. By contrast, PD-1 was not significantly expressed on lymphocytes by treatment with growth factor deprivation, dexamethasone or lipopolysaccharide. These results suggest that the expression of the PD-1 antigen is tightly regulated and induced by signal transduction through the antigen receptor and do not exclude the possibility that the PD-1 antigen may play a role in clonal selection of lymphocytes although PD-1 expression is not required for the common pathway of apoptosis.

Animals↗

PubMed2025

Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy.

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.

Animals↗

PubMed2001

The expanding world of co-stimulation: the two-signal model revisited.

The crucial role for CD28, its homolog CTLA-4 and their binding partners B7-1 and B7-2 in the generation of effective T-cell responses has been well documented. Recently, two new pairs of the CD28/B7 families were identified. The ability of these molecules to regulate T-cell expansion and effector function and the dynamic integration of the co-stimulatory and T-cell receptor signals are just beginning to be explored. Understanding these processes will be crucial for designing clinically relevant approaches to manipulate the adaptive immune system.

Abatacept↗

PubMed2006

Reviving exhausted T lymphocytes during chronic virus infection by B7-H1 blockade.

Cytotoxic T lymphocytes (CTLs) are killer cells that are crucial in the control of viral pathogens and cancers. They can become exhausted during chronic viral infection, a phenomenon that consists of a reduction in both number and functionality of CTLs. Recently, Barber and colleagues demonstrated that B7-H1 (also called PD-L1), a cell-surface molecule that is widely distributed in tissues, was necessary for the maintenance of T-cell exhaustion in a chronic-infection mouse model of lymphocytic choriomeningitis virus (LCMV). PD-1, the receptor of B7-H1, was greatly upregulated on CTLs in response to LCMV, and its expression was maintained during chronic infection. Blockade of the B7-H1-PD-1 pathway by a monoclonal antibody restored CTL function and reduced viral burden. These results suggest a new strategy for the treatment of chronic viral infection.

Animals↗

PubMed2003

Blockade of B7-H1 suppresses the development of chronic intestinal inflammation.

A newly identified costimulatory molecule, programmed death-1 (PD-1), provides a negative signal that is essential for immune homeostasis. However, it has been suggested that its ligands, B7-H1 (PD-L1) and B7-dendritic cells (B7-DC; PD-L2), could also costimulate T cell proliferation and cytokine secretion. Here we demonstrate the involvement of PD-1/B7-H1 and B7-DC interaction in the development of colitis. We first examined the expression profiles of PD-1 and its ligands in both human inflammatory bowel disease and a murine chronic colitis model induced by adoptive transfer of CD4(+)CD45RB(high) T cells to SCID mice. Second, we assessed the therapeutic potential of neutralizing anti-B7-H1 and/or B7-DC mAbs using this colitis model. We found significantly increased expression of PD-1 on T cells and of B7-H1 on T, B, and macrophage/DCs in inflamed colon from both inflammatory bowel disease patients and colitic mice. Unexpectedly, the administration of anti-B7-H1, but not anti-B7-DC, mAb after transfer of CD4(+)CD45RB(high) T cells suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced the production of IFN-gamma, IL-2, and TNF-alpha, but not IL-4 or IL-10, by lamina propria CD4(+) T cells. These data suggest that the interaction of PD-1/B7-H1, but not PD-1/B7-DC, might be involved in intestinal mucosal inflammation and also show a possible role of interaction between B7-H1 and an as yet unidentified receptor for B7-H1 in inducing T cell activation.

Adoptive Transfer↗

PubMed2002

The B7-CD28 superfamily.

The B7-1/B7-2-CD28/CTLA-4 pathway is crucial in regulating T-cell activation and tolerance. New B7 and CD28 molecules have recently been discovered and new pathways have been delineated that seem to be important for regulating the responses of previously activated T cells. Several B7 homologues are expressed on cells other than professional antigen-presenting cells, indicating new mechanisms for regulating T-cell responses in peripheral tissues. Some B7 homologues have unknown receptors, indicating that other immunoregulatory pathways remain to be described. Here, we summarize our current understanding of the new members of the B7 and CD28 families, and discuss their therapeutic potential.

Abatacept↗

PubMed2003

Cytotoxic T-lymphocyte antigen-4 and programmed death-1 function as negative regulators of lymphocyte activation.

The B7 family of ligands and receptors plays a critical role in the modulation of immune responses. The B7/cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the more recently identified programmed death ligand/programmed death-1 (PD-L/PD-1) ligand/receptor pairs define pathways that function as rheostats of lymphocyte activation. Analysis of receptor and ligand expression patterns, as well as the phenotype of CTLA-4 or PD-1-deficient mice, strongly suggests that these pathways are nonredundant. Current data suggest that the B7/CTLA-4 pathway functions primarily to attenuate, limit, and/or terminate naïve T-cell activation in secondary lymphoid organs. The PD-L/PD-1 pathway, on the other hand, may primarily attenuate, limit, and/or terminate T-, B-, and myeloid cell activation/effector function at sites of inflammation in the periphery.

Animals↗

PubMed2001

The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses.

T cell activation is dependent upon signals delivered through the antigen-specific T cell receptor and accessory receptors on the T cell. A primary costimulatory signal is delivered through the CD28 receptor after engagement of its ligands, B7-1 (CD80) or B7-2 (CD86). Engagement of CTLA-4 (CD152) by the same B7-1 or B7-2 ligands results in attenuation of T cells responses. Recently, molecular homologs of CD28 and CTLA-4 receptors and their B7-like ligands have been identified. ICOS is a CD28-like costimulatory receptor with a unique B7-like ligand. PD-1 is an inhibitory receptor, with two B7-like ligands. Additional members of B7 and CD28 gene families have been proposed. Integration of signals through this family of costimulatory and inhibitory receptors and their ligands is critical for activation of immune responses and tolerance. Understanding these pathways will allow development of new strategies for therapeutic intervention in immune-mediated diseases.

Abatacept↗

PubMed2006

Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway.

Estrogen (E2)-induced immunomodulation involves dual effects on antigen-presenting cells (APC) and CD4(+)CD25(+) regulatory T cells (Treg) but not a direct effect on effector T cells. In this report, we further investigated the effects of E2 on APC and Treg function. We found that E2 treatment in vivo strongly reduced recovery of APC from the peritoneal cavity and inhibited induction of the inflammatory cytokines interleukin (IL)-12 and interferon-gamma but enhanced secretion of IL-10. Moreover, E2-conditioned bone marrow-derived dendritic cells (BM-DC) could both enhance Treg activity and directly inhibit responder T cells in the absence of Treg cells. We examined whether this E2-induced inhibitory activity of BM-DC might involve costimulation through the recently described PD-1 pathway. Both E2 and pregnancy markedly enhanced PD-1 expression in several types of APC, including macrophages, B cells, and especially dendritic cells (DC). Similarly to E2-induced enhancement of FoxP3 expression and experimental autoimmune encephalomyelitis protection, E2-induced enhancement of PD-1(+) cells was also mediated through estrogen receptor alpha (Esr1) in DC and macrophages but not in B cells. Based on antibody inhibition studies, PD-1 interaction with its ligands, PDL-1 and especially PDL-2, could mediate either positive or negative regulatory signaling in both mature and immature E2-conditioned DC, depending, respectively, on a relatively high (10:1) or low (1:1) ratio of T cells:BM-DC. These novel findings indicate that E2-induced immunomodulation is mediated in part through potentiation in BM-DC of the PD-1 costimulatory pathway.

Animals↗

PubMed2004

Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger.

Stimulation of certain cytokine and pattern recognition receptors enhances adaptive immune responses, and in chronic situations, may play a role in the loss of self-tolerance. We hypothesized that in addition to upregulating positive immune receptors (i.e. co-stimulatory molecules), certain cytokine and pattern recognition signals might downregulate negative immune receptors, removing a potential barrier to lymphocyte responsiveness. The newly identified CD28 family member Programmed Death-1 (PD-1) is an inhibitory receptor involved in peripheral tolerance, as evidenced by the frank autoimmunity and autoantibody formation found in PD-1-deficient mice. Here we report that antigen-receptor induced PD-1 expression on murine B cells is markedly reduced by certain signals associated with immune system danger, including LPS, CpG oligodeoxynucleotides and several pro-inflammatory cytokines, through distinct signaling pathways. We further report for the first time that engagement of PD-1 inhibits cell cycle progression in primary B cells and that modulation of PD-1 expression by CpG or IL-4 significantly reverses such inhibition. Our data suggest a novel mechanism for enhancement of normal immune responses and disruption of normal tolerance mechanisms.

Animals↗

PubMed1992

Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.

The classical type of programmed cell death is characterized by its dependence on de novo RNA and protein synthesis and morphological features of apoptosis. We confirmed that stimulated 2B4.11 (a murine T-cell hybridoma) and interleukin-3 (IL-3)-deprived LyD9 (a murine haematopoietic progenitor cell line) died by the classical type of programmed cell death. Assuming that common biochemical pathways might be involved in the deaths of 2B4.11 and LyD9, we isolated the PD-1 gene, a novel member of the immunoglobulin gene superfamily, by using subtractive hybridization technique. The predicted PD-1 protein has a variant form of the consensus sequence found in cytoplasmic tails of signal transducing polypeptides associated with immune recognition receptors. The PD-1 gene was activated in both stimulated 2B4.11 and IL-3-deprived LyD9 cells, but not in other death-induced cell lines that did not show the characteristic features of the classical programmed cell death. Expression of the PD-1 mRNA in mouse was restricted to the thymus and increased when thymocyte death was augmented by in vivo injection of anti-CD3 antibody. These results suggest that activation of the PD-1 gene may be involved in the classical type of programmed cell death.

Amino Acid Sequence↗

PubMed2004

New B7 family members with positive and negative costimulatory function.

The B7 family of T-cell costimulatory molecules has expanded considerably in recent years. Among the new costimulatory molecules discovered are inhibitory and activating pathways. Both ligands and receptors often have multiple binding partners, adding to the complexity of T-cell regulation. Some B7 molecules also exhibit reverse signaling, affecting activation of both antigen-presenting cells and T cells. An increased understanding of these pathways of T-cell regulation results in promising new therapeutics because T-cell interference can be better targeted to specific states of activation or location. This will decrease side-effects such as systemic immunosuppression and increase efficiency. Targeting B7 molecular pathways for either inhibiting or increasing cell-mediated immunity has so far shown promising results in models of autoimmunity, transplant rejection and tumor immunotherapy.

Animals↗

PubMed2006

PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion.

Hepatitis C virus (HCV)-specific CD8 cell exhaustion may represent a mechanism of HCV persistence. The inhibitory receptor PD-1 has been reported to be up-regulated in exhausted CD8 cells. Therefore, we studied PD-1 expression longitudinally during acute HCV infection. Most HCV-specific CD8 cells expressed PD-1 at the time of acute illness, irrespective of the final outcome. PD-1 expression declined with the acquisition of a memory phenotype and recovery of an efficient CD8 cell function in resolving HCV infections, whereas high levels were maintained when HCV persisted and HCV-specific CD8 cells remained dysfunctional. Blocking PD-1/PDL-1 interaction with an anti-PDL-1 antibody improved the capacity of expansion of virus-specific CD8 cells.

Antigens, CD↗

PubMed2003

PD-1 inhibits antiviral immunity at the effector phase in the liver.

Unlike naive T cells, effector T cells can be activated by either T cell receptor signal or costimulatory signal alone and therefore the absence of costimulatory molecules on tissue cells cannot explain the tolerance mechanism at the effector phase. Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues. Liver nonparenchymal cells including sinusoidal endothelial cells and Kupffer cells constitutively expressed PD-L1 and inhibited proliferation and cell division of activated T cells expressing PD-1. The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus. These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.

Animals↗