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Results for “Programmed Cell Death 1 Receptor”

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PubMed2001

B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells.

Dendritic cells (DCs), unique antigen-presenting cells (APCs) with potent T cell stimulatory capacity, direct the activation and differentiation of T cells by providing costimulatory signals. As such, they are critical regulators of both natural and vaccine-induced immune responses. A new B7 family member, B7-DC, whose expression is highly restricted to DCs, was identified among a library of genes differentially expressed between DCs and activated macrophages. B7-DC fails to bind the B7.1/2 receptors CD28 and cytotoxic T lymphocyte-associated antigen (CTLA)-4, but does bind PD-1, a receptor for B7-H1/PD-L1. B7-DC costimulates T cell proliferation more efficiently than B7.1 and induces a distinct pattern of lymphokine secretion. In particular, B7-DC strongly costimulates interferon gamma but not interleukin (IL)-4 or IL-10 production from isolated naive T cells. These properties of B7-DC may account for some of the unique activity of DCs, such as their ability to initiate potent T helper cell type 1 responses.

Amino Acid Sequence↗

PubMed2002

New regulatory co-receptors: inducible co-stimulator and PD-1.

Autoreactive lymphocytes are suppressed in healthy individuals by so-called peripheral tolerance. Accumulating evidence indicates that co-receptor signaling plays a pivotal role in the regulation of autoreactive lymphocytes. The positive regulatory co-receptors CD28 and inducible co-stimulator (ICOS) transduce stimulatory cosignals, whereas the negative regulatory co-stimulators CTLA-4 and PD-1 are critical for the regulation of peripheral tolerance and autoimmunity. PD-1 deficient mice develop lupus-like glomerulonephritis and arthritis on a C57Bl/6 background and autoimmune-dilated cardiomyopathy on a BALB/c background.

Abatacept↗

PubMed2002

Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.

B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells. We report here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1. In contrast, B7-H1 is abundant in human carcinomas of lung, ovary and colon and in melanomas. The pro-inflammatory cytokine interferon-gamma upregulates B7-H1 on the surface of tumor cell lines. Cancer cell-associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro, and the apoptotic effect of B7-H1 is mediated largely by one or more receptors other than PD-1. In addition, expression of B7-H1 on mouse P815 tumor increases apoptosis of activated tumor-reactive T cells and promotes the growth of highly immunogenic B7-1(+) tumors in vivo. These findings have implications for the design of T cell-based cancer immunotherapy.

Animals↗

PubMed2026

Localized PD-1 CAR T therapy reprograms neuroinflammation.

B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G+ (IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.

Animals↗

PubMed2004

The deficiency of immunoregulatory receptor PD-1 causes mild osteopetrosis.

Recently, the involvement of immune responses in metabolic bone disease and/or local bone destruction has received much attention. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a member of the immunoglobulin (Ig) superfamily, negatively regulates T cell activation. The deficiency of CTLA-4 induces profound osteopenia with an increase in osteoclastogenesis, suggesting the important role of activated T cells in osteoclastogenesis. Programmed death-1 (PD-1) is the newly identified immunoregulatory receptor, which also belongs to the Ig superfamily. Both CTLA-4 and PD-1 are induced on activated T cells, however, there are no reports linking PD-1 with osteoclasts. In the present study, we have examined the bone phenotype in PD-1-deficient mice PD-1-/- and the role of PD-1 in osteoclastogenesis and osteoclast function. Both trabecular and cortical bone mineral densities of tibia were significantly increased, as observed in peripheral quantitative computed tomography (pQCT), at 12 weeks of age in PD-1-/- mice. Histomorphometric analysis of the PD-1-/- mice and the age-matched controls at 12 weeks of age showed a 2-fold increase in bone volume (BV/TV) with a 55% decrease in osteoclast number (N.Oc/BS). Bone formation indices were similar in both groups. The number of soluble receptor activator of nuclear factor kappaB ligand (sRANKL)-induced osteoclast-like cells (OCLs) derived from the PD-1-deficient splenocytes was significantly decreased (by 25%). On the other hand, PD-1 deficiency did not affect the bone-resorbing activity of mature osteoclasts. Our results suggest that PD-1 deficiency reduces osteoclastogenesis resulting in an osteopetrotic phenotype. Identical members of the Ig superfamily, CTLA-4 and PD-1, which negatively regulate immune responses, may differentially affect osteoclastogenesis and bone remodeling.

Animals↗

PubMed2005

Role of the programmed death-1 pathway in regulation of alloimmune responses in vivo.

Programmed death-1 (PD-1), an inhibitory receptor up-regulated on activated T cells, has been shown to play a critical immunoregulatory role in peripheral tolerance, but its role in alloimmune responses is poorly understood. Using a novel alloreactive TCR-transgenic model system, we examined the functions of this pathway in the regulation of alloreactive CD4+ T cell responses in vivo. PD-L1, but not PD-1 or PD-L2, blockade accelerated MHC class II-mismatched skin graft (bm12 (I-Abm12) into B6 (I-Ab)) rejection in a similar manner to CTLA-4 blockade. In an adoptive transfer model system using the recently described anti-bm12 (ABM) TCR-transgenic mice directly reactive to I-Abm12, PD-1 and PD-L1 blockade enhanced T cell proliferation early in the immune response. In contrast, at a later time point preceding accelerated allograft rejection, only PD-L1 blockade enhanced T cell proliferation. In addition, PD-L1 blockade enhanced alloreactive Th1 cell differentiation. Apoptosis of alloantigen-specific T cells was inhibited significantly by PD-L1 but not PD-1 blockade, indicating that PD-1 may not be the receptor for the apoptotic effect of the PD-L1-signaling pathway. Interestingly, the effect of PD-L1 blockade was dependent on the presence of CD4+ CD25+ regulatory T cells in vivo. These data demonstrate a critical role for the PD-1 pathway, particularly PD-1/PD-L1 interactions, in the regulation of alloimmune responses in vivo.

Adoptive Transfer↗

PubMed2006

Regulated compartmentalization of programmed cell death-1 discriminates CD4+CD25+ resting regulatory T cells from activated T cells.

More effective discrimination between CD4+CD25+ regulatory T cells (Treg) and activated T cells would significantly improve the current level of purification of Treg and their therapeutic application. We observed that approximately 90% of Treg (positive for the nuclear transcription factor Forkhead winged helix protein-3 and able to inhibit naive T cell proliferation) isolated from the spleens or lymph nodes of normal mice did not express significant levels of the inhibitory receptor programmed cell death-1 (PD-1) on their surface, but retained PD-1 intracellularly. An identical phenotype was also identified for human CD4+CD25(high) T cells isolated from peripheral blood of healthy volunteers. By contrast, activated T cells expressed high levels of surface PD-1 that paralleled up-regulation of CD25 during effector cell expansion. This distinction allowed us to isolate CD4+CD25+PD-1(-) T cells with suppressive activity from mice immunized with mature allogeneic dendritic cells. Although purification was limited to resting Treg because TCR ligation induced up-regulation of surface PD-1, this strategy nevertheless represents a valuable step toward more definitive characterization of Treg and their improved purification for therapeutic assessment.

Amino Acid Sequence↗

PubMed2001

Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice.

Dilated cardiomyopathy is a severe pathology of the heart with poorly understood etiology. Disruption of the gene encoding the negative immunoregulatory receptor PD-1 in BALB/c mice, but not in BALB/c RAG-2-/- mice, caused dilated cardiomyopathy with severely impaired contraction and sudden death by congestive heart failure. Affected hearts showed diffuse deposition of immunoglobulin G (IgG) on the surface of cardiomyocytes. All of the affected PD-1-/- mice exhibited high-titer circulating IgG autoantibodies reactive to a 33-kilodalton protein expressed specifically on the surface of cardiomyocytes. These results indicate that PD-1 may be an important factor contributing to the prevention of autoimmune diseases.

Animals↗

PubMed2002

Negative co-receptors on lymphocytes.

The past year has seen significant advances in our understanding of critical roles of negative immunoregulatory signals delivered through the B7-CD28 superfamily in regulating T cell activation and tolerance. Structural data on CTLA-4 have provided novel insights into the inhibitory functions of CTLA-4. Initial characterization of the PD-1-PD-1-ligand pathway has revealed that this pathway can downregulate TCR- and CD28-mediated signals. Recent studies indicate that ICOS exerts distinct effects at different phases of an immune response: ICOS can inhibit as well as stimulate T cell responses.

Abatacept↗

PubMed2004

PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells.

Since metastasis is the major cause of death for cancer patients, there is an urgent need to develop new therapies to control hematogenous dissemination of cancer cells. Previously we and others demonstrated a novel mechanism that allows tumors to escape from the host immune response by expressing PD-L1 which can negatively regulate immune response through the interaction with PD-1, an immunoinhibitory receptor belonging to the CD28 family. In this study, we report that hematogenous spread of poorly immunogenic B16 melanoma cells to the liver was inhibited in PD-1-deficient mice. After inoculation to spleen, PD-L1 was induced on tumor cells, which did not express PD-L1 in vitro. As compared with wild-type mice, intrasplenic injection of B16 cells into PD-1-deficient mice showed enhanced induction of effector T cells in spleen, prolonged T cell proliferation and cytokine production, and augmented homing of effector T cells to tumor sites in the liver, resulting in accumulation of effector T cells in the tumor sites. PD-1 blockade by genetic manipulation or antibody treatment inhibited not only hematogenous dissemination of B16 melanoma cells to the liver on the C57BL/6 background, but also dissemination of CT26 colon cancer cells to the lung on the BALB/c background. These results suggest that PD-1 blockade may be a powerful tool for treatment of hematogenous spread of various tumor cells.

Animals↗

PubMed2005

Costimulation: critical pathways in the immunologic regulation of asthma.

T cells play an important role in the pathogenesis of allergy and asthma. T-cell receptor engagement by antigenic peptides presented to major histocompatibility complex (MHC) class II molecules and activation of costimulatory molecules are crucial in the regulation of T-cell immune responses. Costimulatory molecules are responsible for second signals that induce T-cell activation and proliferation. The best characterized costimulatory pathways include CD80/CD86 interacting with CD28, and a number of additional costimulatory molecules have recently been identified, including members of the tumor necrosis family. The positive signals induced by these molecules are counterbalanced by other members of the costimulatory family, including cytotoxic T lymphocyte-associated antigen (CTLA)-4, programmed death (PD)-1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. In this review, we describe the fundamental properties of costimulatory molecules and address the influence of costimulatory signals on allergic responses.

Antigens, CD↗

PubMed2002

Microanatomical localization of PD-1 in human tonsils.

PD-1 is an immunoinhibitory receptor, which belongs structurally to the CD28 family. PD-1-deficient mice show breakdown of peripheral tolerance and manifest multiple autoimmune symptoms. We previously described expression of PD-1 on activated T and B lymphocytes and myeloid cells. However, little is known about the microanatomical distribution of PD-1 in lymphoid organs. In this study, we performed immunohistochemistry using monoclonal antibodies against human PD-1. In human tonsils, PD-1 was expressed on most of T cells and a small subset of centrocytes in the light zone of germinal centers (GCs), where clonal selection of centrocytes takes place. These results suggest that PD-1 may play an important role in GC reaction.

Adolescent↗

PubMed2004

PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta.

Engagement of the immunoinhibitory receptor, programmed death-1 (PD-1) attenuates T-cell receptor (TCR)-mediated activation of IL-2 production and T-cell proliferation. Here, we demonstrate that PD-1 modulation of T-cell function involves inhibition of TCR-mediated phosphorylation of ZAP70 and association with CD3zeta. In addition, PD-1 signaling attenuates PKCtheta activation loop phosphorylation in a cognate TCR signal. PKCtheta has been shown to be required for T-cell IL-2 production. A phosphorylated PD-1 peptide, corresponding to the C-terminal immunoreceptor tyrosine-switch motif (ITSM), acts as a docking site in vitro for both SHP-2 and SHP-1, while the phosphorylated peptide containing the N-terminal PD-1 immunoreceptor tyrosine based inhibitory motif (ITIM) associates only with SHP-2.

Amino Acid Sequence↗

PubMed2002

Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.

Animals↗

PubMed2004

Structural and functional analysis of the costimulatory receptor programmed death-1.

PD-1, a member of the CD28/CTLA-4/ICOS costimulatory receptor family, delivers negative signals that have profound effects on T and B cell immunity. The 2.0 A crystal structure of the extracellular domain of murine PD-1 reveals an Ig V-type topology with overall similarity to the CTLA-4 monomer; however, there are notable differences in regions relevant to function. Our structural and biophysical data show that PD-1 is monomeric both in solution as well as on cell surface, in contrast to CTLA-4 and other family members that are all disulfide-linked homodimers. Furthermore, our structure-based mutagenesis studies identify the ligand binding surface of PD-1, which displays significant differences compared to those present in the other members of the family.

Amino Acid Sequence↗

PubMed2006

Cutting Edge: Programmed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens.

Constitutive presentation of tissue Ags by dendritic cells results in tolerance of autoreactive CD8+ T cells; however, the underlying molecular mechanisms are not well understood. In this study we show that programmed death (PD)-1, an inhibitory receptor of the CD28 family, is required for tolerance induction of autoreactive CD8+ T cells. An antagonistic Ab against PD-1 provoked destructive autoimmune diabetes in RIP-mOVA mice expressing chicken OVA in the pancreatic islet cells, which received naive OVA-specific CD8+ OT-I cells. This effect was mediated by the PD ligand (PD-L) PD-L1 but not by PD-L2. An increased number of effector OT-I cells recovered from the pancreatic lymph nodes of anti-PD-L1-treated mice showed down-regulation of PD-1. Furthermore, the blockade of PD-1/PD-L1 interaction during the priming phase did not significantly affect OT-I cell division but enhanced its granzyme B, IFN-gamma, and IL-2 production. Thus, during the presentation of tissue Ags to CD8+ T cells, PD-1/PD-L1 interaction crucially controls the effector differentiation of autoreactive T cells to maintain self-tolerance.

Animals↗

PubMed2006

Delivering PD-1 inhibitory signal concomitant with blocking ICOS co-stimulation suppresses lupus-like syndrome in autoimmune BXSB mice.

BXSB mice spontaneously develop an autoimmune syndrome characterized by hypergammaglobulinemia, autoantibody production, and the development of fatal glomerulonephritis that closely resembles systemic lupus erythematosus (SLE) in humans. While blocking positive T cell co-stimulation has shown effectiveness in preventing the onset of murine lupus, deliberate delivering negative co-stimulation to halt unwanted T and B cell activation has not been tested. We developed a recombinant adenovirus containing the full-length mouse PD-L1 gene (Ad.PD-L1) to engage the immunoinhibitory receptor PD-1 on activated lymphocytes to prevent lupus nephritis in BXSB mice. This strategy was further reinforced by concomitant injection of anti-ICOSL(B7h) mAb to block ICOS-mediated co-stimulation. The combined therapy dramatically delayed the onset of proteinuria, effectively inhibited IgG autoantibody production, and significantly reduced hypercellularity and deposition of IgG in glomeruli, resulting in almost complete amelioration of lupus nephritis in these animals. Our results indicate the therapeutic potential of simultaneous stimulation of PD-1-mediated pathway and blockade of ICOS-B7h co-stimulation in the prevention of human lupus nephritis.

Adenoviridae↗

PubMed2005

In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses.

B7-DC, one of the recently described B7 family members, has the capacity to inhibit T cell responses via engagement of the immunoreceptor tyrosine-based inhibitory motif-containing inhibitory PD-1 receptor as well as enhance responses via an as yet unidentified costimulatory receptor. B7-DC is highly homologous to a coinhibitory B7 family member, B7-H1, which also binds PD-1. It is currently unclear which B7-DC function-costimulation or inhibition-predominates in vivo. To study in vivo functions of B7-DC, we evaluated immune responses in B7-DC knockout (KO) mice. Although not eliminated, interferon-gamma (IFN-gamma) production by CD4 T cells and IFN-gamma-dependent humoral responses were reduced in B7-DC KO mice relative to wild type mice. Antigen-specific CD8 T cell responses and cytotoxic T lymphocyte (CTL) activity were also diminished in B7-DC KO mice. Hepatic tumors grew more quickly in B7-DC KO mice, associated with a decrease in intrahepatic tumor-specific CD8 T cells. These results highlight the contrasting in vivo roles of B7-DC and B7-H1 and indicate that B7-DC functions as a tuning molecule, selectively augmenting T helper 1 and CTL responses.

Animals↗