Details for: TNFSF18

Gene ID: 8995

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: TNFSF18

Ensembl ID: ENSG00000120337

Description: TNF superfamily member 18

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 4.71
    rCSI 5.71%
    PRS 96.76
  • basal cell of epidermis CL0002187
    CSI 2.57
    rCSI 4.56%
    PRS 95.61

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

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  • Node Size: Proportional to Target Cell CSI magnitude
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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 [TNFSF18](/details-gene/8995) (Tumor Necrosis Factor Superfamily Member 18), also known as Glucocorticoid-Induced TNF Receptor-Related Protein Ligand (GITRL), is a protein-coding gene located on chromosome 1q25.1. As a member of the TNF superfamily, it functions as a type II transmembrane protein and cytokine that plays a significant role in the regulation of the adaptive immune system. **Overall** expression data highlight [TNFSF18](/details-gene/8995) as a key marker for specific T cell populations, particularly [CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203), and it is also notably expressed in non-immune cells such as the [basal cell of epidermis](/details-cell/CL0002187). Its primary function involves binding to its receptor, TNFRSF18 (GITR), to modulate T cell proliferation, survival, and effector functions, making it a critical player in immune homeostasis and response. ## Cellular Roles and Expression Landscape The expression profile of [TNFSF18](/details-gene/8995) underscores its specialized function within the immune system and at epithelial barriers. **Overall**, the gene's significance is most pronounced in [CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203) (CSI: 4.71), indicating a crucial role in the biology of memory T lymphocytes. This is consistent with its established function as an activation-inducible ligand that co-stimulates T cell responses ([Link](https://doi.org/10.1074/jbc.274.10.6056)). The expression of a co-stimulatory ligand on T cells themselves may suggest a mechanism for T cell-T cell communication or self-amplification loops during an immune response. Interestingly, [TNFSF18](/details-gene/8995) also shows significant expression in [basal cell of epidermis](/details-cell/CL0002187) (CSI: 2.57). This suggests a role beyond inter-lymphocyte communication, potentially mediating crosstalk between the skin's structural barrier and the immune system. For instance, research has shown that signaling through its receptor can promote leukocyte adhesion by upregulating adhesion molecules on other cell types ([Link](https://doi.org/10.1124/jpet.113.207605)), a function that may be relevant for immune cell recruitment to the skin during inflammation. ## Pathways and Molecular Function The functional annotations for [TNFSF18](/details-gene/8995) confirm its role as a key signaling molecule in the immune system. Its involvement in biological processes such as the [adaptive immune response](/details-go/GO:0002250), [T cell proliferation involved in immune response](/details-go/GO:0002309), and [positive regulation of leukocyte migration](/details-go/GO:0002687) directly aligns with its expression pattern in memory T cells. As a cytokine ([GO:0005125](https://www.ebi.ac.uk/QuickGO/term/GO:0005125)), [TNFSF18](/details-gene/8995) binds to its cognate receptor ([GO:0032813](https://www.ebi.ac.uk/QuickGO/term/GO:0032813)) to initiate downstream signaling. This is part of the broader [Cytokine signaling in immune system](/details-reactome/R-HSA-1280215) pathway. The engagement of its receptor triggers the [Tumor necrosis factor-mediated signaling pathway](/details-go/GO:0033209), which includes the [positive regulation of nf-kappab transcription factor activity](/details-go/GO:0051092) and the [Tnfr2 non-canonical nf-kb pathway](/details-reactome/R-HSA-5668541). This activation cascade is central to modulating gene expression programs that control cell survival, proliferation, and inflammation. Studies have also indicated its expression on myeloid dendritic cells can enhance their immunostimulatory capabilities ([Link](https://doi.org/10.1189/jlb.0906568)). ## Research Directions Based on its distinct expression profile and known functions, several research avenues for [TNFSF18](/details-gene/8995) emerge, particularly concerning its dual roles in T cell regulation and epithelial-immune communication. **Testable Hypotheses:** 1. Given its high expression on memory CD8+ T cells and its co-stimulatory function, [TNFSF18](/details-gene/8995) signaling may be critical for the maintenance and reactivation of long-term viral or tumor-specific memory T cell populations. Dysregulation of this pathway could contribute to T cell exhaustion in chronic disease settings. 2. The expression of [TNFSF18](/details-gene/8995) by [basal cell of epidermis](/details-cell/CL0002187) may serve as an 'alarmin' signal. During skin injury or infection, its upregulation on basal cells could act locally to recruit and activate skin-resident T cells, initiating a rapid, localized immune response. **Proposed Experiment:** To test the second hypothesis regarding the role of [TNFSF18](/details-gene/8995) in epidermal-immune crosstalk, a human skin organoid or 3D skin equivalent model could be employed. CRISPR-Cas9 could be used to knock out [TNFSF18](/details-gene/8995) in primary human keratinocytes used to form the epidermal layer. These knockout and control models would then be challenged with inflammatory stimuli (e.g., poly(I:C) or UV radiation). The subsequent recruitment and activation of co-cultured, autologous T cells could be quantified using advanced imaging and flow cytometry. Furthermore, RNA-sequencing of the keratinocytes would reveal how [TNFSF18](/details-gene/8995) loss affects the local chemokine and cytokine milieu following a pro-inflammatory challenge. **Therapeutic Potential:** [TNFSF18](/details-gene/8995) and its receptor GITR represent a highly attractive immunomodulatory axis for therapeutic intervention. * **Activation:** Agonistic antibodies or recombinant forms of [TNFSF18](/details-gene/8995) could be used to stimulate GITR, thereby enhancing anti-tumor T cell responses. This strategy could be particularly effective in combination with checkpoint inhibitors to overcome T cell anergy and promote tumor clearance. * **Inhibition:** Conversely, in the context of autoimmune diseases or graft-versus-host disease where excessive T cell activation is pathogenic, blocking the TNFSF18-GITR interaction with an antagonistic monoclonal antibody could be a viable therapeutic strategy to dampen effector T cell function and restore immune tolerance.

Genular Protein ID: 3929190417

Symbol: TNF18_HUMAN

Name: Activation-inducible TNF-related ligand

UniProtKB Accession Codes:

Q9UNG2 A9IQG8 O95852 Q6ISV1

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 10 Ensembl 1 EvolutionaryTrace 1 GO 18 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 2 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 7 PDBsum 7 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

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: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

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: 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: 17449724

Title: Expression of human GITRL on myeloid dendritic cells enhances their immunostimulatory function but does not abrogate the suppressive effect of CD4+CD25+ regulatory T cells.

PubMed ID: 17449724

DOI: 10.1189/jlb.0906568

PubMed ID: 23892569

Title: Glucocorticoid-induced tumor necrosis factor receptor family-related ligand triggering upregulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and promotes leukocyte adhesion.

PubMed ID: 23892569

DOI: 10.1124/jpet.113.207605

PubMed ID: 18040044

Title: Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: implications for function.

PubMed ID: 18040044

DOI: 10.1073/pnas.0709264104

Sequence Information:

  • Length: 177
  • Mass: 20308
  • Checksum: 3D78CE6B90F4C9E3
  • Sequence:
    • MCLSHLENMP LSHSRTQGAQ RSSWKLWLFC SIVMLLFLCS FSWLIFIFLQ LETAKEPCMA 
KFGPLPSKWQ MASSEPPCVN KVSDWKLEIL QNGLYLIYGQ VAPNANYNDV APFEVRLYKN 
KDMIQTLTNK SKIQNVGGTY ELHVGDTIDL IFNSEHQVLK NNTYWGIILL ANPQFIS

Genular Protein ID: 1884639073

Symbol: A0A0U5JXL4_HUMAN

Name: N/A

UniProtKB Accession Codes:

A0A0U5JXL4

Database IDs:

AlphaFoldDB 1 BioGRID-ORCS 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 6 Gene3D 1 InterPro 2 KEGG 1 NCBI Taxonomy 1 OMA 1 OrthoDB 1 PANTHER 2 PhylomeDB 1 RefSeq 1 SAM 1 SMR 1 SUPFAM 1 VEuPathDB 1

Citations:

PubMed ID: 26646413

Title: Comparative genomic analysis of eutherian tumor necrosis factor ligand genes.

PubMed ID: 26646413

DOI: 10.1007/s00251-015-0887-5

Title: Eutherian third-party data gene collections.

DOI: 10.1016/j.genrep.2019.100414

Sequence Information:

  • Length: 199
  • Mass: 22724
  • Checksum: C83A94645745DA58
  • Sequence:
    • MTLHPSPITC EFLFSTALIS PKMCLSHLEN MPLSHSRTQG AQRSSWKLWL FCSIVMLLFL 
CSFSWLIFIF LQLETAKEPC MAKFGPLPSK WQMASSEPPC VNKVSDWKLE ILQNGLYLIY 
GQVAPNANYN DVAPFEVRLY KNKDMIQTLT NKSKIQNVGG TYELHVGDTI DLIFNSEHQV 
LKNNTYWGII LLANPQFIS