Details for: TNFRSF18

Gene ID: 8784

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: TNFRSF18

Ensembl ID: ENSG00000186891

Description: TNF receptor superfamily member 18

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • CD8-positive, CD28-negative, alpha-beta regulatory T cell CL0000920
    CSI 18.85
    rCSI 37.59%
    PRS 97.36
  • activated CD4-positive, alpha-beta T cell CL0000896
    CSI 17.53
    rCSI 16.21%
    PRS 98.18
  • early lymphoid progenitor CL0000936
    CSI 11.46
    rCSI 10.07%
    PRS 95.58
  • IgA plasma cell CL0000987
    CSI 10.83
    rCSI 11.08%
    PRS 93.89
  • intraepithelial lymphocyte CL0002496
    CSI 10.46
    rCSI 28.48%
    PRS 97.92
  • group 3 innate lymphoid cell CL0001071
    CSI 10.05
    rCSI 7.55%
    PRS 95.25
  • immature B cell CL0000816
    CSI 9.68
    rCSI 7.19%
    PRS 97.18
  • secretory cell CL0000151
    CSI 8
    rCSI 8.35%
    PRS 92.31
  • regulatory T cell CL0000815
    CSI 6.77
    rCSI 7.85%
    PRS 87.35
  • CD16-negative, CD56-bright natural killer cell, human CL0000938
    CSI 6.03
    rCSI 4.52%
    PRS 98.1
  • precursor B cell CL0000817
    CSI 5.98
    rCSI 5.23%
    PRS 95.75
  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI 5.61
    rCSI 4.03%
    PRS 98.51
  • natural T-regulatory cell CL0000903
    CSI 5.58
    rCSI 10.57%
    PRS 98.76
  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 5.05
    rCSI 3.37%
    PRS 96.99
  • mature T cell CL0002419
    CSI 5.02
    rCSI 3.9%
    PRS 98.15
  • activated CD8-positive, alpha-beta T cell, human CL0001049
    CSI 4.94
    rCSI 8.45%
    PRS 97.16
  • central memory CD8-positive, alpha-beta T cell CL0000907
    CSI 4.77
    rCSI 3.22%
    PRS 98.62
  • CD4-positive, alpha-beta thymocyte CL0000810
    CSI 4.67
    rCSI 3.74%
    PRS 95.56
  • innate lymphoid cell CL0001065
    CSI 4.49
    rCSI 9.26%
    PRS 87.6
  • CD4-positive helper T cell CL0000492
    CSI 4.45
    rCSI 3.36%
    PRS 98.1
  • Langerhans cell CL0000453
    CSI 4.39
    rCSI 6.71%
    PRS 97.36
  • IgG plasma cell CL0000985
    CSI 4.22
    rCSI 5.06%
    PRS 95.55
  • T follicular helper cell CL0002038
    CSI 3.75
    rCSI 2.81%
    PRS 98.1
  • activated CD8-positive, alpha-beta T cell CL0000906
    CSI 3.63
    rCSI 3.57%
    PRS 97.42
  • keratinocyte CL0000312
    CSI 3.06
    rCSI 2.56%
    PRS 92.81
  • mononuclear phagocyte CL0000113
    CSI 3.02
    rCSI 6.64%
    PRS 95.31
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell CL0000792
    CSI 2.9
    rCSI 2.85%
    PRS 98.44
  • T-helper 17 cell CL0000899
    CSI 2.73
    rCSI 2.17%
    PRS 98.7
  • nasal mucosa goblet cell CL0002480
    CSI 2.69
    rCSI 3.12%
    PRS 93.16
  • activated type II NK T cell CL0000931
    CSI 2.62
    rCSI 2.94%
    PRS 98.05
  • decidual natural killer cell, human CL0002343
    CSI 2.17
    rCSI 22.05%
    PRS 96.63
  • fraction A pre-pro B cell CL0002045
    CSI 2.15
    rCSI 2.46%
    PRS 95.79
  • common lymphoid progenitor CL0000051
    CSI 2.07
    rCSI 2.76%
    PRS 98.26
  • club cell CL0000158
    CSI 2.06
    rCSI 3.01%
    PRS 89.6
  • respiratory basal cell CL0002633
    CSI 1.77
    rCSI 1.84%
    PRS 94.32
  • T-helper 1 cell CL0000545
    CSI 1.72
    rCSI 3.1%
    PRS 98.07
  • activated CD4-positive, alpha-beta T cell, human CL0001043
    CSI 1.53
    rCSI 3.68%
    PRS 98.25
  • helper T cell CL0000912
    CSI 1.36
    rCSI 1.93%
    PRS 88.85
  • basal cell of epithelium of trachea CL1000348
    CSI 1.34
    rCSI 9.49%
    PRS 93.42
  • group 2 innate lymphoid cell CL0001069
    CSI 0.94
    rCSI 5.06%
    PRS 98.24

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [TNFRSF18](/details-gene/8784), or Tumor Necrosis Factor Receptor Superfamily Member 18, is a protein-coding gene located on chromosome 1p36.33. It is also widely known as Glucocorticoid-Induced TNFR-Related protein (GITR). As a member of the TNF-receptor superfamily, [TNFRSF18](/details-gene/8784) functions as a key co-stimulatory receptor involved in immune system regulation, particularly in the modulation of T cell responses. Initial studies identified it as a novel activation-inducible receptor in T lymphocytes ([Link](https://doi.org/10.1074/jbc.274.10.6056), [Link](https://doi.org/10.1016/s0960-9822(99)80093-1)). Expression data indicates its profound significance across various lymphoid cell lineages. **Overall**, it shows the highest significance in T cell subsets, including [CD8-positive, CD28-negative, alpha-beta regulatory T cell](/details-cell/CL0000920) and [activated CD4-positive, alpha-beta T cell](/details-cell/CL0000896), underscoring its dual role in both immune activation and suppression. ## Cellular Roles and Expression Landscape The expression profile of [TNFRSF18](/details-gene/8784) firmly establishes it as a critical component of the lymphoid immune system. Its significance is most pronounced in T lymphocyte populations, where it appears to function in both effector and regulatory contexts. - **T Cell Regulation and Activation:** The gene's highest significance scores are observed in [CD8-positive, CD28-negative, alpha-beta regulatory T cell](/details-cell/CL0000920) (CSI: 18.85) and [activated CD4-positive, alpha-beta T cell](/details-cell/CL0000896) (CSI: 17.53). This highlights its established dual functionality: providing co-stimulatory signals to activated effector T cells while also being a key marker and functional molecule for [regulatory T cell](/details-cell/CL0000815)s. Its high relevance in other T cell types like [intraepithelial lymphocyte](/details-cell/CL0002496) and [CD4-positive, alpha-beta memory T cell](/details-cell/CL0000897) further supports a broad role in T cell biology. - **B Cell and Innate Lymphoid Cell Involvement:** Beyond T cells, [TNFRSF18](/details-gene/8784) shows significant expression in the B cell lineage, including [IgA plasma cell](/details-cell/CL0000987) and [immature B cell](/details-cell/CL0000816). This suggests a potential role in humoral immunity, particularly in mucosal contexts where IgA is predominant. Furthermore, its expression in [group 3 innate lymphoid cell](/details-cell/CL0001071) and both CD56-bright and CD56-dim natural killer cell subsets points towards a broader function in innate immune responses. - **Specificity of Expression:** The top-ranked cells are almost exclusively of hematopoietic origin, particularly from the lymphoid lineage. The notable absence of non-immune cell types like neurons, muscle cells, or epithelial cells in the high-significance list underscores its specialized function within the immune system. ## Pathways and Molecular Function Functional annotations for [TNFRSF18](/details-gene/8784) are highly consistent with its expression pattern and its identity as a co-stimulatory receptor. As a receptor located on the [external side of plasma membrane](/details-cell/GO:0009897), its primary molecular function is [tumor necrosis factor receptor activity](/details-cell/GO:0005031). Biologically, it is integral to the '[immune system](/details-cell/R-HSA-168256)' and '[cytokine signaling in immune system](/details-cell/R-HSA-1280215)' pathways. Its signaling is implicated in diverse cellular outcomes, including the '[negative regulation of apoptotic process](/details-cell/GO:0043066)' which promotes lymphocyte survival, and the '[positive regulation of leukocyte migration](/details-cell/GO:0002687)'. The gene's role in T cell biology is precisely defined by its involvement in the Reactome pathway '[Runx1 and foxp3 control the development of regulatory t lymphocytes (tregs)](https://reactome.org/content/detail/R-HSA-8877330)'. This directly corroborates the finding of its high significance in [regulatory T cell](/details-cell/CL0000815) populations. Engagement of the receptor likely triggers downstream signaling cascades such as the '[Tnfr2 non-canonical nf-kb pathway](https://reactome.org/content/detail/R-HSA-5668541)', a key pathway for cell survival and activation. ## Research Directions The data highlights [TNFRSF18](/details-gene/8784) as a central regulator of lymphocyte function, making it a subject of intense research, particularly in immunology and oncology. Based on its expression profile and known functions, several research avenues can be proposed. **Proposed Hypotheses:** 1. Given its high significance in both [activated CD4-positive, alpha-beta T cell](/details-cell/CL0000896) and multiple regulatory T cell subsets, signaling through [TNFRSF18](/details-gene/8784) is context-dependent: in effector T cells, it primarily delivers a co-stimulatory signal to augment proliferation and cytokine production, whereas in [regulatory T cell](/details-cell/CL0000815)s, it acts to maintain their suppressive phenotype and stability. 2. The high significance of [TNFRSF18](/details-gene/8784) in [IgA plasma cell](/details-cell/CL0000987) suggests a previously underappreciated role in mucosal immunity. Ligation of [TNFRSF18](/details-gene/8784) on these cells may promote their survival, terminal differentiation, or enhance IgA production at mucosal surfaces. **Experimental Approach:** To test the first hypothesis regarding the context-dependent role of [TNFRSF18](/details-gene/8784) in T cells, a co-culture suppression assay could be employed. [Regulatory T cell](/details-cell/CL0000815)s and conventional CD4+ T cells (Tconv) would be isolated from human PBMCs. The [TNFRSF18](/details-gene/8784) gene would be knocked out in Treg and Tconv populations separately using CRISPR-Cas9. The suppressive capacity of knockout Tregs versus wild-type Tregs could be assessed by measuring the proliferation (e.g., via CFSE dilution) of Tconv cells in a co-culture system following T-cell receptor stimulation. This would directly determine the necessity of [TNFRSF18](/details-gene/8784) for Treg-mediated suppression. **Therapeutic Potential:** As a cell surface receptor predominantly expressed on immune cells, [TNFRSF18](/details-gene/8784) is an outstanding therapeutic target. Its ability to co-stimulate effector T cells while potentially abrogating Treg suppression makes it a prime candidate for cancer immunotherapy. The therapeutic strategy would focus on **activation** rather than inhibition. The development of agonistic monoclonal antibodies that bind to and activate [TNFRSF18](/details-gene/8784) could simultaneously boost anti-tumor T cell responses and overcome the immunosuppressive tumor microenvironment, representing a promising approach to treat various malignancies.

Genular Protein ID: 1663282157

Symbol: TNR18_HUMAN

Name: Tumor necrosis factor receptor superfamily member 18

UniProtKB Accession Codes:

Q9Y5U5 B1AME1 O95851 Q5U0I4 Q9NYJ9

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 1 CTD 1 ChEMBL 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 10 Ensembl 3 ExpressionAtlas 1 GO 10 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PRINTS 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 Reactome 2 RefSeq 3 SMART 1 SMR 1 STRING 1 SignaLink 1 SwissPalm 1 TopDownProteomics 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10074428

Title: Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR.

PubMed ID: 10074428

DOI: 10.1016/s0960-9822(99)80093-1

PubMed ID: 10037686

Title: Identification of a novel activation-inducible protein of the tumor necrosis factor receptor superfamily and its ligand.

PubMed ID: 10037686

DOI: 10.1074/jbc.274.10.6056

PubMed ID: 10836847

Title: Identification of three novel mRNA splice variants of GITR.

PubMed ID: 10836847

DOI: 10.1038/sj.cdd.4400670

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15340161

Title: Signal peptide prediction based on analysis of experimentally verified cleavage sites.

PubMed ID: 15340161

DOI: 10.1110/ps.04682504

Sequence Information:

  • Length: 241
  • Mass: 26000
  • Checksum: 90DC3B4AA7E82CBE
  • Sequence:
    • MAQHGAMGAF RALCGLALLC ALSLGQRPTG GPGCGPGRLL LGTGTDARCC RVHTTRCCRD 
YPGEECCSEW DCMCVQPEFH CGDPCCTTCR HHPCPPGQGV QSQGKFSFGF QCIDCASGTF 
SGGHEGHCKP WTDCTQFGFL TVFPGNKTHN AVCVPGSPPA EPLGWLTVVL LAVAACVLLL 
TSAQLGLHIW QLRSQCMWPR ETQLLLEVPP STEDARSCQF PEEERGERSA EEKGRLGDLW 
V

Genular Protein ID: 846333318

Symbol: A0A0R7FDM1_HUMAN

Name: N/A

UniProtKB Accession Codes:

A0A0R7FDM1

Database IDs:

AlphaFoldDB 1 BioGRID-ORCS 1 CDD 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 4 Gene3D 1 InterPro 4 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 1 PeptideAtlas 1 RefSeq 1 SAM 2 SMART 2

Sequence Information:

  • Length: 347
  • Mass: 36682
  • Checksum: 730C97255CDD13A2
  • Sequence:
    • MAQHGAMGAF RALCGLALLC ALSLGQRPTG GPGCGPGRLL LGTGTDARCC RVHTTRCCRD 
YPGEECCSEW DCMCVQPEFH CGDPCCTTCR HHPCPPGQGV QSQGKFSFGF QCIDCASGTF 
SGGHEGHCKP WTDCTQFGFL TVFPGNKTHN AVCVPGSPPA EPLGWLTVVL LAVAACVLLL 
TSAQLGLHIW QLRSQCMWPR GLSQPGAGRW EHGCLLTVAP LQRPSCCWRC RRRPKTPEAA 
SSPRKSGASD RQRRRGGWET CGCEPGRPPG PPTAASPSPG APQAAGALRS ALGRALLPWQ 
QKWVQEGGSD QRPGPCSSAA AAGPCRRERE TQSWPPSSLA GPDGVGS