TNFSF18 (tumor necrosis factor (ligand) superfamily, member 18)

2010-04-01   Theresa Placke , Hans-Georg Kopp , Benjamin Joachim Schmiedel , Helmut Rainer Salih 

Eberhard Karls University of Tuebingen, Department of Hematology\\\/Oncology, Otfried-Mueller-Str. 10, 72076 Tuebingen, Germany




Atlas Image
Figure 1. Schematic illustration of the gene structure of human TNFSF18 on chromosome 1. Both published transcript variants are shown. Red boxes represent the mRNA transcript within the gene. The smaller boxes at the beginning and the end of the transcripts indicate untranslated regions, while the larger boxes display the translated parts.


2 transcript versions published:
mRNA 748 bp: 3 exons (1-223, 224-254, 255-748) -> coding for 199 aa (2-601),
mRNA 610 bp: 3 exons (1-176, 177-207, 208-610) -> coding for 177 aa (21-554).


Accurate start codon is not clearly defined, 2 transcript versions are published (differing start codons in exon 1).




Atlas Image
Figure 2. Schematic illustration of the structure of TNFSF18 protein versions, according to the two published transcripts.


TNFSF18/GITR ligand (GITRL) is a single-pass type II transmembrane protein and contains 2 potential glycosylation sites (predicted at 129 aa and 161 aa). TNFSF18 encompasses 177 or 199 aa and thus has a molecular weight of about 20 kDa. In the 177 aa long version, amino acids 1-28 constitute the cytoplasmic domain, 29-49 the transmembrane domain, and 50-177 the extracellular domain, whereas in the 199 aa long variant the amino acids 1-50 constitute the cytoplasmic domain, 51-71 the transmembrane domain, and 72-199 the extracellular domain.


TNFSF18 is expressed on DC, monocytes, macrophages, B cells, activated T cells, endothelial cells, osteoclasts and various healthy non-lymphoid tissues (e.g., testis, ...). The fact that TNFSF18 is constitutively expressed on resting antigen-presenting cells distinguishes it from most other TNF family members, which are not detectable in resting state and are upregulated following activation.
In addition, TNFSF18 is constitutively expressed and released as soluble form by solid tumors of different histological origin and various hematopoietic malignancies.


TNFSF18 is a type II transmembrane protein. A soluble form of the molecule has been shown to be released by a yet unknown mechanism e.g. by tumor cells.


TNFSF18 is the only known ligand for GITR (TNFRSF18, AITR), which is mainly expressed by lymphatic cells like T lymphocytes and NK cells. Upon interaction with its receptor, TNFSF18 is, like many other TNF family members, capable to transduce bidirectional signals, i.e. in the receptor and the ligand bearing cell. Transduction of signals into TNFSF18 bearing cells has been shown to cause differentiation of osteoclasts, to activate macrophages and to alter cytokine production of healthy myeloid cells, but also of carcinoma and leukemia cells and influences apoptosis. Activation of macrophages via TNFSF18 results in increased secretion of inflammatory mediators like MMP-9, NO and TNF. In healthy macrophages and myeloid leukemia cells, TNFSF18 signaling has been found to involve the MAP kinase pathway.
Binding to TNFRSF18 may induce signaling through this receptor, which, in mice, has been implicated in the development of autoimmune diseases, graft versus host disease and in the immune response against infectious pathogens and tumors.
Available data suggest that TNFRSF18 may mediate different effects in mice and men, and most functional studies regarding the role of TNFRSF18 in tumor immunology have been performed using agonistic antibodies or injection of adenovirus expressing recombinant TNFSF18 into tumors, which might not reflect the consequences of TNFRSF18 interaction with its natural ligand in vivo. In line, studies evaluating immune responses in GITR-/- mice have so far not led to a clear picture of the role of TNFRSF18 in normal physiology.


The TNFSF18 gene is conserved in human, chimpanzee, dog, mouse, and rat. The homology among the other TNF family members is highest with OX40L.



No published single nucleotide polymorphisms (SNPs).

Implicated in

Entity name
Host-tumor interaction
In mice, it has been shown that application of the agonistic GITR antibody DTA-1 delays tumor progression and can even lead to complete tumor rejection. Similar results were obtained by using GITRL-Fc fusion protein. Transfection of tumor cells with GITRL causes rejection of the tumor and prolonged survival, while parental cells cannot be rejected. This effect can be reversed by administration of a blocking GITRL antibody. There is evidence that expression of GITRL promotes the development of tumor-specific T cells. Re-challenge of mice which once successfully rejected GITRL-positive tumor results in complete rejection of both transfected and non-transfected tumors. Several studies showed increased infiltration of CD8+ cells in GITRL-expressing tumors. By the use of depletion experiments and athymic nude mice it has been shown that for GITR-GITRL dependent rejection of tumors both CD4+ and CD8+ T cells as well as NK cells are required.
In humans, controversial data regarding the function of GITR and GITRL in tumor immunology were described. Hanabuchi et al. reported that NK cells are activated by engagement of GITRL on plasmacytoid dendritic cells, which can be blocked by anti-GITRL antibody. In contrast, Baltz et al. and Baessler et al. demonstrated substantial GITRL expression on tumor cells and leukemic blasts resulting in diminished NK cell reactivity. Blockade of GITR-GITRL interaction by anti-GITR antibody abrogated the inhibitory effect of GITRL. Furthermore, stimulation of GITRL substantially induced the production of TGF-beta and IL-10 by tumor cells and leukemic blasts. Additionally, they reported that human GITRL is released by tumor cells in a soluble form which impairs NK cell reactivity alike the membrane-bound form. Thus, GITRL expression seems to affect the interaction of human tumor cells with the immune system by influencing tumor cell immunogenity and metastasis and creating an immunosuppressive cytokine microenvironment. The inhibitory effect of GITRL on human NK cells was further supported by Liu et al., who reported inhibition of NK cell proliferation and cytokine production and increased apoptosis after GITR stimulation. These controversial data regarding the function of GITR on human NK cells may be due to the usage of different reagents and different experimental condition.
The results regarding the role of GITR and GITRL in tumor immunology are controversial in mice and humans. Thus, GITR and GITRL may mediate different effects in mice and men, and in line suppression of human regulatory T cells, in contrast to their murine counterparts, is not inhibited by GITR. Many studies employed agonistic antibodies or recombinant protein for GITR stimulation and not constitutively GITRL-expressing cells. Thus, these studies do not involve possible influences of reverse signaling mediated by GITRL, which may change reaction of GITRL-bearing cells and may in turn alter functions of GITR-bearing cells.
Entity name
Autoimmune disease
The influence of GITR and GITRL was tested in different mouse models of autoimmune disease. Onset of autoimmune diabetes in NOD mice is accelerated if they are treated with agonistic GITR mAb, and activation of CD4+ T cells is increased compared to control treated mice. Likewise, application of a blocking GITRL antibody protected from diabetes. In GITR -/- mice, experimental autoimmune diseases take an attenuated course. GITR -/- mice with collagen-induced arthritis show less joint inflammation and bone erosion than wildtype mice. Furthermore, lower concentrations of inflammatory mediators were reported. In line with these findings, GITR triggering antibody exacerbates collagen-induced arthritis in wildtype mice compared to control-treated siblings.
However, all these studies regarding the function of GITR and its ligand in autoimmune disease were performed in mice. Further investigation is needed to elucidate the relevance of GITR and GITR ligand in human autoimmune disease and to clarify the similarities and differences of these molecules in mice and men.


Pubmed IDLast YearTitleAuthors
176027482008Reverse signaling initiated from GITRL induces NF-kappaB activation through ERK in the inflammatory activation of macrophages.Bae EM et al
191553052009Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand subverts immunosurveillance of acute myeloid leukemia in humans.Baessler T et al
186895452008Neutralization of tumor-derived soluble glucocorticoid-induced TNFR-related protein ligand increases NK cell anti-tumor reactivity.Baltz KM et al
169551812006Glucocorticoid-induced tumour necrosis factor receptor (GITR) and its ligand (GITRL) in atopic dermatitis.Baumgartner-Nielsen J et al
154727132005Bypassing tumor-associated immune suppression with recombinant adenovirus constructs expressing membrane bound or secreted GITR-L.Calmels B et al
190185332009Localized expression of GITR-L in the tumor microenvironment promotes CD8+ T cell dependent anti-tumor immunity.Cho JS et al
166514472006Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity.Cohen AD et al
171353592007Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation.Cuzzocrea S et al
193518572009Immune rejection of mouse tumors expressing mutated self.Duan F et al
159442932005Glucocorticoid-induced TNF receptor, a costimulatory receptor on naive and activated T cells, uses TNF receptor-associated factor 2 in a novel fashion as an inhibitor of NF-kappa B activation.Esparza EM et al
198770172010Inhibition of murine gammadelta lymphocyte expansion and effector function by regulatory alphabeta T cells is cell-contact-dependent and sensitive to GITR modulation.Gonçalves-Sousa N et al
174176512007Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy.Grohmann U et al
100744281999Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR.Gurney AL et al
163971342006Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL).Hanabuchi S et al
183464592008GITR ligand-costimulation activates effector and regulatory functions of CD4+ T cells.Igarashi H et al
151287592004Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression.Ji HB et al
165205572006Prevention of chronic graft-versus-host disease by stimulation with glucocorticoid-induced TNF receptor.Kim J et al
161861872005Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells.Ko K et al
100376861999Identification of a novel activation-inducible protein of the tumor necrosis factor receptor superfamily and its ligand.Kwon B et al
126165412003Soluble glucocorticoid-induced tumor necrosis factor receptor (sGITR) increased MMP-9 activity in murine macrophage.Lee HS et al
182306092008Glucocorticoid-induced tumor necrosis factor receptor negatively regulates activation of human primary natural killer (NK) cells by blocking proliferative signals and increasing NK cell apoptosis.Liu B et al
168747372006Expression of GITR ligand abrogates immunosuppressive function of ocular tissue and differentially modulates inflammatory cytokines and chemokines.Mahesh SP et al
152495932004GITR activation induces an opposite effect on alloreactive CD4(+) and CD8(+) T cells in graft-versus-host disease.Muriglan SJ et al
186326502008Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling.Nishikawa H et al
91771971997A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis.Nocentini G et al
162850152005Glucocorticoid-induced TNFR family-related protein (GITR) activation exacerbates murine asthma and collagen-induced arthritis.Patel M et al
196043022009Enhancement of T-cell-mediated anti-tumour immunity via the ectopically expressed glucocorticoid-induced tumour necrosis factor receptor-related receptor ligand (GITRL) on tumours.Piao J et al
167098002006Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity.Ramirez-Montagut T et al
179476652007Glucocorticoid-induced TNFR-related protein lowers the threshold of CD28 costimulation in CD8+ T cells.Ronchetti S et al
118129902002Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance.Shimizu J et al
150035062004The soluble glucocorticoid-induced tumor necrosis factor receptor causes cell cycle arrest and apoptosis in murine macrophages.Shin HH et al
128580162003Induction of nitric oxide synthase (NOS) by soluble glucocorticoid induced tumor necrosis factor receptor (sGITR) is modulated by IFN-gamma in murine macrophage.Shin HH et al
124784772002GITR interacts with the pro-apoptotic protein Siva and induces apoptosis.Spinicelli S et al
146080362003Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells.Tone M et al
192725912009The GITRL-GITR system alters TLR-4 expression on DC during fungal infection.Vecchiarelli A et al
157715652005TNF/TNFR family members in costimulation of T cell responses.Watts TH et al
199362382009Key role of the GITR/GITRLigand pathway in the development of murine autoimmune diabetes: a potential therapeutic target.You S et al
180251802007Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors.Zhou P et al

Other Information

Locus ID:

NCBI: 8995
MIM: 603898
HGNC: 11932
Ensembl: ENSG00000120337


dbSNP: 8995
ClinVar: 8995
TCGA: ENSG00000120337


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Cytokine-cytokine receptor interactionKEGGhsa04060
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
TNFR2 non-canonical NF-kB pathwayREACTOMER-HSA-5668541
TNFs bind their physiological receptorsREACTOMER-HSA-5669034


Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
163971342006Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL).42
189242132008Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR/GITR-L interaction, IL-10 and TGF-beta.35
173608482007Cancer immunoediting by GITR (glucocorticoid-induced TNF-related protein) ligand in humans: NK cell/tumor cell interactions.29
180400442007Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function.29
203313782010Large-scale candidate gene analysis of spontaneous clearance of hepatitis C virus.29
202374962010New genetic associations detected in a host response study to hepatitis B vaccine.27
194235402009Common variation in genes related to innate immunity and risk of adult glioma.19
176027482008Reverse signaling initiated from GITRL induces NF-kappaB activation through ERK in the inflammatory activation of macrophages.18
186895452008Neutralization of tumor-derived soluble glucocorticoid-induced TNFR-related protein ligand increases NK cell anti-tumor reactivity.18


Theresa Placke ; Hans-Georg Kopp ; Benjamin Joachim Schmiedel ; Helmut Rainer Salih

TNFSF18 (tumor necrosis factor (ligand) superfamily, member 18)

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

Online version: