Alternative titles; symbols
HGNC Approved Gene Symbol: PDCD1
Cytogenetic location: 2q37.3 Genomic coordinates (GRCh38): 2:241,849,884-241,858,894 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.3 | {Multiple sclerosis, disease progression, modifier of} | 126200 | Multifactorial | 3 |
| {Systemic lupus erythematosus, susceptibility to, 2} | 605218 | 3 |
The PDCD1 gene encodes a cell surface receptor that is a member of the B7 (see CD80; 112203)/CD28 (186760) superfamily involved in immunomodulation. PDCD1 acts as an inhibitory molecule on T cells after interacting with its ligands PDL1 (605402) and PDL2 (605723) (Kroner et al., 2005).
Programmed cell death (PCD) is essential for generation of the complex structural and functional organization of various organs and systems in the living organism. Most of the cells undergoing PCD require transcriptional activation of genes that are essential for cell death. Ishida et al. (1992) isolated cDNA encoding PD1, a cell surface membrane protein of the immunoglobulin superfamily. In the mouse, they found that PD1 is strongly induced in thymus when an anti-CD3 antibody is injected and a large number of thymocytes are killed. Although the precise function of the PD1 protein was unknown, strong correlation of its expression with programmed cell death suggested a role in that phenomenon. Shinohara et al. (1994) isolated and characterized the human homolog of the mouse gene by screening a human T-cell cDNA library with the mouse probe. The deduced amino acid sequence was 60% identical to the mouse counterpart and a putative tyrosine kinase-association motif was well conserved.
Finger et al. (1997) reported the complete cDNA sequence of the PDCD1 gene. The full-length cDNA is 2,106 bp long and encodes a predicted protein of 288 amino acids. The human and mouse genes share 70% homology at the nucleotide level and 60% homology at the amino acid level. The mouse homolog was preferentially expressed in pro-B cells from adult mouse bone marrow. Finger et al. (1997) concluded from these and other data that the PDCD1 gene may play a role in B-cell differentiation during the pro-B cell stage.
Finger et al. (1997) determined that the PDCD1 gene contains 5 exons.
By fluorescence in situ hybridization, Shinohara et al. (1994) mapped the PDCD1 gene to 2q37.3. Finger et al. (1997) confirmed the assignment to 2q37.
Freeman et al. (2000) demonstrated that the B7H1 gene (605402), which they termed 'programmed cell death-1 ligand-1,' bound to PDCD1 and resulted in negative regulation of lymphocyte activation. In mouse cells, Latchman et al. (2001) demonstrated that the Pdl2 protein bound to human PDCD1, resulting in inhibition of T-cell proliferation and cytokine production.
Using microarray analysis and flow cytometry, Barber et al. (2006) found that Pd1 was highly upregulated by functionally exhausted CD8 (see 186910) T cells from mice infected with a lymphocytic choriomeningitis virus (LCMV) strain causing chronic infection, but not by functional memory CD8 T cells from mice infected with an LCMV strain causing acute infection. FACS analysis showed that Pd1 expression was transiently upregulated on CD8 T cells in acutely infected mice. In contrast, Pd1 expression continued to rise and was sustained on virus-specific CD8 T cells in chronically infected mice. Pdl1 was highly expressed on virally infected cells. Treatment of chronically infected mice with a blocking antibody to Pdl1 enhanced CD8 T-cell function, leading to cytotoxic T-cell activity, production of Ifng (147570) and Tnf (191160), and substantially reduced virus levels with no overt signs of disease. The beneficial effects of Pdl1 blockade were also observed in mice depleted of helper CD4 (186940) T cells. Expression of Pd1 was not affected by anti-Pdl1 treatment, and CD8 T-cell function did not decline after cessation of treatment. Pdl1 -/- mice chronically infected with LCMV died due to immunopathologic damage, whereas Pdl1 -/- mice acutely infected with LCMV behaved like wildtype mice. Barber et al. (2006) concluded that antibody blockade of PDL1 (605402) may be an effective immunologic strategy for treatment of chronic viral infections, including human immunodeficiency virus, and virus-induced cancers, although the potential for autoimmunity and immunopathology must be carefully monitored.
To investigate the role of PD1 in a chronic human viral infection, Day et al. (2006) examined PD1 expression from human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade C-infected people who were naive to anti-HIV treatments, using 10 major histocompatibility complex class 1 tetramers specific for frequently targeted epitopes. They reported that PD1 is significantly upregulated on those cells and that expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicated that the immunoregulatory PD1/PDL1 pathway is operative during a persistent viral infection in humans, and defined a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.
Using flow cytometric analysis, Said et al. (2010) found that expression of PD1 was upregulated on CD16 (146740)-positive and CD16-negative monocytes, but not on dendritic cells, in viremic HIV-positive patients, but not in highly active antiretroviral therapy (HAART)-treated HIV-positive patients. PD1 upregulation in monocytes was induced by microbial Toll-like receptor (TLR; see 603030) ligands and inflammatory cytokines. In HIV-positive patients, PD1 expression on CD16-positive or CD16-negative monocytes correlated with blood IL10 (124092) concentrations. Furthermore, triggering of PD1 by PDL1, but not by PDL2, induced monocyte IL10 production. PD1 triggering inhibited CD4-positive T-cell responses. IL10 stimulation increased STAT3 (102582) phosphorylation in CD4-positive T cells, and both CD4-positive and CD8-positive T lymphocytes showed increased PD1 expression in viremic HIV patients. Said et al. (2010) proposed that both IL10-IL10R (146933) and PD1-PDL1 interactions need to be blocked to restore the immune response during HIV infection.
Dai et al. (2010) noted that CD8-positive/CD122 (IL2RB; 146710)-positive T cells have been shown to function, paradoxically, as both regulatory and memory T cells. Using flow cytometric analysis, they demonstrated that mouse Cd8-positive/Cd122-positive T cells included both Pd1-positive and Pd1-negative subpopulations. Only the Pd1-positive subpopulation suppressed T-cell responses in vitro and in vivo, and this suppression occurred largely in an Il10-dependent manner. Il10 production, in turn, was dependent on costimulatory signaling of both Cd28 and Pd1. Cd8-positive/Cd122-positive/Pd1-negative T cells mediated skin graft rejection. Dai et al. (2010) concluded that CD8-positive/CD122-positive T cells can be either regulatory or memory T cells, depending on their PD1 expression and antigen specificity.
By analyzing gene expression in sorted CD8-positive T cells specific for the HIV-1 Gag protein from HIV-positive individuals, Quigley et al. (2010) showed that the PD1 inhibitory receptor coordinately upregulated a program of genes in 'exhausted' CD8-positive T cells. The program included upregulation of the transcription factor BATF (612476). Enforced expression of BATF was sufficient to impair T-cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD1 inhibition. BATF silencing in T cells from individuals with chronic viremia rescued HIV-specific T-cell function. Quigley et al. (2010) concluded that inhibitory receptors can cause T-cell exhaustion by upregulating genes, such as BATF, that inhibit T-cell function and may be targets to improve T-cell immunity to HIV.
Kawamoto et al. (2012) provided evidence that the inhibitory co-receptor PD1 regulates the gut microbiota through appropriate selection of IgA plasma cell repertoires. PD1 deficiency generates an excess number of T follicular helper cells with altered phenotypes, which results in dysregulated selection of IgA precursor cells in the germinal center of Peyer patches. Consequently, the IgAs produced in PD1-deficient mice have reduced bacteria-binding capacity, which causes alterations of microbial communities in the gut. Kawamoto et al. (2012) concluded that PD1 plays a critical role in regulation of antibody diversification required for the maintenance of intact mucosal barrier.
Using flow cytometry, Yang et al. (2013) examined expression of PD1 and PDL1 on cervical T cells and dendritic cells, respectively, from 40 women who were either positive or negative for high-risk human papillomavirus (HR-HPV) infection with different grades of cervical intraepithelial neoplasia (CIN). They found that PD1 and PDL1 expression was associated with HR-HPV positivity and that expression increased with increasing CIN grade. In contrast, expression of the CD80 and CD86 (601020) costimulatory markers decreased in HR-HPV-positive women in parallel with increasing CIN grade. Similarly, increased levels of the Th2 cytokine IL10 and decreased levels of the Th1 cytokines IFNG and IL12 (161560) in cervical exudates correlated with HR-HPV positivity and increased CIN grade. Yang et al. (2013) proposed that upregulation of the inhibitory PD1/PDL1 pathway may negatively regulate cervical cell-mediated immunity to HPV and contribute to progression of HR-HPV-related CIN.
Pauken et al. (2016) investigated whether PD1 pathway blockade, which can reinvigorate exhausted T cells and improve control of infections and cancer, could also reprogram cells to become durable memory T cells. They found that reinvigoration of exhausted T cells by Pd1 pathway blockade in mice was transitory, with T-cell exhaustion returning if antigen concentration remained high. Exhausted T cells had a distinct epigenetic profile compared with effector T cells and memory T cells, and the profile changed little after Pd1 pathway blockade, although exhausted T cells did acquire some features of effector T-cell biology.
Sen et al. (2016) defined the accessible chromatin profile in exhausted mouse and human CD8-positive T cells and found that it was distinct from memory CD8-positive T cells. Genome editing in mouse T cells showed that Pd1 expression was regulated, in part, by an exhaustion-specific enhancer containing essential Rar (see 180240), Tbet (TBX21; 604895), and Sox3 (313430) motifs.
Gordon et al. (2017) demonstrated that both mouse and human tumor-associated macrophages (TAMs) express PD1. TAM PD1 expression increased over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD1 expression correlated negatively with phagocytic potency against tumor cells, and blockade of PD1-PDL1 (605402) in vivo increased macrophage phagocytosis, reduced tumor growth, and lengthened the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggested that PD1-PDL1 therapies may also function through a direct effect on macrophages.
George et al. (2017) reported a treatment-naive patient with metastatic uterine leiomyosarcoma who had experienced complete tumor remission for more than 2 years on anti-PD1 monotherapy. By immunohistochemical, RNA sequencing, and whole-exome sequencing analyses, they analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue and identified biallelic PTEN (601728) loss and changes in neoantigen expression in the resistant tumor. PD1-positive cell infiltration was significantly decreased in the resistant tumor. Patient T cells responded vigorously to the neoantigens in vitro. George et al. (2017) concluded that PTEN mutations and reduced neoantigen expression are potential mediators of resistance to immune checkpoint therapy.
Le et al. (2017) evaluated the efficacy of PD1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. Le et al. (2017) concluded that their data supported the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers makes them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.
Wartewig et al. (2017) showed that the acute enforcement of oncogenic T-cell receptor (TCR) signaling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genomewide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor PD1, as a master gene that suppresses oncogenic T cell signaling. Mono- and biallelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD1 enhances levels of the tumor suppressor PTEN and attenuates signaling by the kinases AKT (164730) and PKC (see 176960) in premalignant cells. By contrast, a homo- or heterozygous deletion of PD1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD1 receptor is a potent haploinsufficient tumor suppressor in T cell lymphomas that is frequently altered in human disease.
Meng et al. (2018) reported a mechanism of PD1 degradation and the importance of this mechanism in antitumor immunity in preclinical models. They showed that surface PD1 undergoes internalization, subsequent ubiquitination, and proteasome degradation in activated T cells. FBXO38 (608533) is an E3 ligase of PD1 that mediates lys48-linked polyubiquitination and subsequent proteasome degradation. Conditional knockout of Fbxo38 in T cells did not affect T cell receptor and Cd28 signaling, but led to faster tumor progression in mice owing to higher levels of Pd1 in tumor-infiltrating T cells. Anti-PD1 therapy normalized the effect of Fbxo38 deficiency on tumor growth in mice, which suggested that PD1 is the primary target of FBXO38 in T cells. In human tumor tissues and a mouse cancer model, transcriptional levels of FBXO38 and Fbxo38, respectively, were downregulated in tumor-infiltrating T cells. However, Il2 (147680) therapy rescued Fbxo38 transcription and therefore downregulated Pd1 levels in Pd1-positive T cells in mice. Meng et al. (2018) concluded that FBXO38 regulates PD1 expression and highlighted an alternative method to block the PD1 pathway.
Sugiura et al. (2019) demonstrated that CD80 (112203) interacts with PDL1 (605402) in cis on antigen-presenting cells to disrupt PDL1/PD1 binding. Subsequently, PDL1 cannot engage PD1 to inhibit T cell activation when antigen-presenting cells express substantial amounts of CD80. In knockin mice in which cis-PDL1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD1. Sugiura et al. (2019) concluded that CD80 on antigen-presenting cells limits the PD1 coinhibitory signal while promoting CD28 (186760)-mediated costimulation, and highlighted critical components for induction of optimal immune responses.
Systemic lupus erythematosus is a complex autoimmune disease that affects approximately 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE had been suggested in different populations. One of these susceptibility loci, SLEB2 (605218), was reported in Nordic multicase families. Within this region, the PDCD1 gene was considered the strongest candidate for association with the disease. Prokunina et al. (2002) analyzed 2,510 individuals, including members of 5 independent sets of families as well as unrelated individuals affected with SLE, for SNPs that they had identified in PDCD1. They showed that one intronic SNP (600244.0001) was associated with development of SLE in Europeans and Mexicans. The associated allele of this SNP alters a binding site for the RUNT-related transcription factor-1 (RUNX1; 151385) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.
Kroner et al. (2005) reported an association between the PDCD1 7146G-A polymorphism (600244.0001) and disease progression in multiple sclerosis (MS; 126200).
Nishimura et al. (2001) generated mice deficient in PD1 by targeted disruption. Pd1 -/- mice bred on a BALB/c background developed dilated cardiomyopathy with severely impaired contraction and sudden death by congestive heart failure. Affected hearts showed diffuse deposition of immunoglobulin G on the surfaces of cardiomyocytes. All of the affected Pd1 -/- mice exhibited high-titer circulating IgG autoantibodies reactive to a 33-kD protein expressed specifically on the surface of cardiomyocytes. Pd1 -/- mice bred on a BALB/c Rag2 (179616) -/- background did not develop cardiomyopathy, suggesting that the development of the heart disease in the BALB/c Pd1 -/- mice can be attributed to the functions of T and/or B lymphocytes. Preliminary studies by Nishimura et al. (2001) showed that the disease could be successfully transferred into Rag2 -/- mice with spleen or bone marrow cells from diseased mice. Nishimura et al. (2001) concluded that PD1 may be an important factor contributing to the prevention of autoimmune diseases.
Okazaki et al. (2003) followed up on the finding that mice lacking Pd1 develop autoimmune dilated cardiomyopathy, with production of high-titer autoantibodies against a heart-specific, 30-kD protein. They purified the protein from heart extract and identified it as cardiac troponin I, which is encoded by the Tnni3 gene (191044). Mutation in the TNNI3 gene can cause familial hypertrophic cardiomyopathy (192600). Administration of monoclonal antibodies to Tnni3 induced dilatation and dysfunction of hearts in wildtype mice.
Okazaki et al. (2005) evaluated BALB/c double-knockout (DKO) mice lacking both Fcgr2b (604590) and Pdcd1. They observed no enhanced frequency of dilated cardiomyopathy, as was seen in Pdcd1 -/- BALB/c mice, but instead found that over one-third of the DKO mice without cardiomyopathy underwent weight loss. Necropsy revealed 2-fold enlargement of both kidneys with translucent renal pelves, indicating obstruction of urinary flow. The ureter showed enlargement only at the ureteropelvic junction. Despite a normal appearance, bladders were nearly devoid of urine. Histopathologic analysis indicated that the hydronephrotic mice had severe inflammation along the urinary tract. Immunohistopathologic analysis demonstrated antiurothelial antibodies, and Western blot analysis showed that the antibodies recognized uroplakin-3 (UPK3A; 611559). Okazaki et al. (2005) concluded that Fcgr2b and Pdcd1 cooperatively regulate autoimmune phenotypes in mice and that mouse background strain is likely to be critical for observing the phenotype. They proposed that BALB/c Fcg2b/Pdcd1 DKO mice may serve as a good model for similar complications observed in SLE and Sjogren syndrome (see 270150).
Using a lethal model of histoplasmosis, Lazar-Molnar et al. (2008) showed that all Pd1-deficient mice survived challenge with Histoplasma capsulatum, whereas wildtype mice died with disseminated disease. Infection induced an upregulation of Pdl on macrophages and splenocytes. Macrophages from infected mice inhibited T-cell activation in vitro. Antibody blocking Pd1 significantly increased survival of lethally infected mice. Lazar-Molnar et al. (2008) concluded that the PD1-PDL pathway has a key role in the regulation of antifungal immunity and may be a target for immunotherapy.
Prokunina et al. (2002) identified a 7146G-A regulatory polymorphism (see AF363458), which they called PD-1.3, in an intronic enhancer in the PDCD1 gene. They found an association between susceptibility to SLE (605218) and the G allele. The presence of adenine (A) disrupted the predicted DNA-binding site for RUNX1 (151385) in the first repeat; specific binding occurred when guanine (G) was present at this site. The enhancer-like structure in intron 4 of PDCD1 containing the G/A SNP includes 4 imperfect tandem repeats containing binding sites for transcription factors exclusively involved in hematopoietic differentiation and inflammation, including RUNX1. Prokunina et al. (2002) proposed that RUNX1 binds to the wildtype PDCD1 enhancer to modulate transcription of PDCD1. On cellular activation with self-antigen, the wildtype enhancer may provide a rapid increase in PDCD1 expression, and PDCD1, containing an immunoreceptor tyrosine-based inhibitory motif, inhibits autoreactive cells and preserves self-tolerance. Disruption of the RUNX1 binding site by the presence of adenine could lead to aberrant regulation of PDCD1, contributing to the dysregulated self-tolerance and to the chronic lymphocyte hyperactivity characteristic of SLE. Alternatively, the defect in PDCD1 expression may take place during early lymphocyte development.
Among 939 German patients with multiple sclerosis (MS; 126200), Kroner et al. (2005) reported an association between the A allele of the PD-1.3 polymorphism and disease progression. Of 94 patients with primary progressive MS, 44% had the G/G genotype, and 53% had the A/G genotype. Of 5 MS patients who were homozygous for the A allele, 3 had primary progressive MS, and 1 had secondary progressive MS. In vitro studies showed that PDCD1-mediated inhibition of T-cell activation and cytokine secretion was impaired in cells from patients with the A allele compared to cells from patients with only the G allele. Presence of the A allele did not confer susceptibility to disease development.
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