Tumor necrosis factor ligand superfamily member 9 also known as 4-1BB ligand or 4-1BBL or CD137L is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the TNFSF9
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
4-1BBL is a type 2
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
receptor that is found on APCs (antigen presenting cells) and binds to
4-1BB (also known as CD137). The 4-1BB/4-1BBL complex belongs to the
TNFR
The tumor necrosis factor receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain. With the exception of nerve growth ...
:
TNF
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
superfamily,
which is expressed on activated
T Lymphocytes
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
.
Structure of 4-1BB/4-1BBL complex
The 4-1BB/4-1BBL complex consists of three monomeric 4-1BBs bound to a trimeric 4-1BBL. Each 4-1BB monomer binds to two 4-1BBLs via cysteine-rich domains (CRDs). The interaction between 4-1BB and the second 4-1BBL is required to stabilize their interactions. The link with 4-1BBL is largely made up of amino acids from the dynamic loops of the CRD2 and the β sheet of CRD3 of 4-1BB, according to a detailed study of the binding between the 4-1BB and 4-1BBL interface. CRD2 amino acids (T61, Q67, and K69) interact with the AA′ loop (Y110 and G114) and the intra-H-strand loop (Q227 and Q230) of 4-1BBL to form various hydrogen bond interactions.
Application to cancer immunotherapy
Studies on the poorly immunogenic Ag104A sarcoma and the extremely tumorigenic P815 mastocytoma provided the first systematic proof that anti-4-1BB antibodies have potent anti-tumor effects. Anti-4-1BB administration to mice with the aforementioned tumors was shown to substantially inhibit tumor growth by increasing CTL activity. In the years to come, more studies verified and legitimized the effect of 4-1BB signaling to inhibit tumor growth.
The interaction between 4-1BB and 4-1BBL provide
costimulatory signals to a variety of
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s, which can be used to discover cancer immunotherapy. The 4-1BB/4-1BBL complex together with a signal provided by a T-cell receptor can provide costimulatory signals to
CD4+ and
CD8+ T cells in mice, leading to the activation of
CD4+ and
CD8+ T cells. The activation of
CD8+ T cells is essential in antitumor immunity.
The 4-1BB/4-1BBL complex with the help of T-cell receptor signals can co-stimulate human CD28
− T cells and trigger the increase in CD28
− T cells. Unlike the activation of
CD8+ T cells, the proliferation of CD28
− T cells can negatively affect cancer state and other diseases. Therefore, this pathway can be targeted for immunotherapy.
See also
*
CD137
CD137 is a member of the tumor necrosis factor (TNF) receptor family. Its alternative names are ''tumor necrosis factor receptor superfamily member 9'' (TNFRSF9), 4-1BB and ''induced by lymphocyte activation'' (ILA). It is of interest to immunolog ...
References
External links
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