Immunoglobulin superfamily

The immunoglobulin superfamily (IgSF) is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on shared structural features with immunoglobulins (also known as antibodies); they all possess a domain known as an immunoglobulin domain or fold. Members of the IgSF include cell surface antigen receptors, co-receptors and co-stimulatory molecules of the immune system, molecules involved in antigen presentation to lymphocytes, cell adhesion molecules and certain cytokine receptors. They are commonly associated with roles in the immune system.

Immunoglobulin domains
Proteins are classified into the IgSF if they possess a structural domain known as an immunoglobulin (Ig)-domain. Ig-domains are named after the immunoglobulin molecules, in which they were first discovered. They contain about 70-110 amino acids and are categorized into different types according to their size and function. Ig-domains possess a characteristic Ig-fold that is a “sandwich”-like structure formed by two sheets of antiparallel beta strands. Interactions between charged amino acids on the inward face of the sandwich and disulphide bonds formed between cysteine residues, which are conserved in almost all Ig domains, stabilize the Ig-fold. One end of the Ig domain houses a section called the complementarity determining region that is important for the specificity of IgSF members for their ligands. The major types of Ig-domain are the variable (or IgV)-domain and the constant (or IgC)-domain. IgV-domains are generally longer (with 9 beta-strands) than IgC-domains (with 7 beta-strands). However, there are some Ig domains that fall into different categories. The Ig domains of some IgSF members resemble IgV-domains in their amino acid composition, yet are similar in size to IgC-domains. These are called IgC2-domains, while standard IgC-domains are called IgC1-domains. Other Ig domains exist that are called intermediate (or I)-domains.

Antigen receptors and ligands
Antigen receptors found on the surface of T and B lymphocytes in all jawed vertebrates belong to the IgSF. Immunoglobulin molecules (the antigen receptors of B cells) are the founding members of the IgSF. In humans, there are five distinct types of immunoglobulin molecule all containing a heavy chain with four Ig domains and a light chain with two Ig domains. The antigen receptor of T cells is the T cell receptor (TCR), which is composed of two chains, either the TCR-alpha and -beta chains, or the TCR-delta and gamma chains. All TCR chains contain two Ig domains in the extracellular portion; one IgV domain at the N-terminus and one IgC1 domain adjacent to the cell membrane. The ligands for TCRs are major histocompatibility complex (MHC) proteins. These come in two forms; MHC class I forms a dimer with a molecule called beta-2 microglobulin (β2M) and interacts with the TCR on cytotoxic T cells and MHC class II has two chains (alpha and beta) that interact with the TCR on helper T cells. MHC class I, MHC class II and β2M molecules all possess Ig domains and are therefore also members of the IgSF.

Co-receptors and accessory molecules
Other molecules on the surfaces of T cells also interact with MHC molecules during TCR engagement. These are known as co-receptors. In lymphocyte populations, the co-receptor CD4 is found on helper T cells and the co-receptor CD8 is found on cytotoxic T cells. CD4 has four Ig domains in its extracellular portion and functions as a monomer. CD8, in contrast, functions as a dimer with either two identical alpha chains or, more typically, with an alpha and beta chain. CD8-alpha and CD8-beta each has one extracellular IgV domain in its extracellular portion. A further molecule is found on the surface of T cells that is also involved in signaling from the TCR. CD3 is a molecule that helps to transmit a signal from the TCR following its interaction with MHC molecules. Three different chains make up CD3 in humans, the gamma chain, delta chain and epsilon chain, all of which are IgSF molecules with a single Ig domain. Similar to the situation with T cells, B cells also have cell surface co-receptors and accessory molecules that assist with cell activation by the B Cell Receptor (BCR)/immunoglobulin. Two chains are used or signaling, CD79a and CD79b that both possess a single Ig domain. A co-receptor complex is also used by the BCR, including CD19, an IgSF molecule with two IgC2-domains.

Co-stimulatory or inhibitory molecules
Co-stimulatory and inhibitory signaling receptors and ligands control the activation, expansion and effector functions of cells. One major group of IgSF co-stimulatory receptors are molecules of the CD28 family; CD28, CTLA-4, program death-1 (PD-1), the B- and T-lymphocyte attenuator (BTLA, CD272), and the inducible T-cell co-stimulator (ICOS, CD278); and their IgSF ligands belong to the B7 family; CD80 (B7-1), CD86 (B7-2), ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1).

CD28 is expressed on T cells and can bind to either the CD80 (B7-1) or CD86 (B7-2) ligands that are expressed on professional antigen presenting cells, like dendritic cells, macrophages and activated B cells. These same two ligands are shared by the receptor CTLA-4 that inhibits of CD28-dependent T cell responses, and are also members of the IgSF. CTLA-4 is expressed on the surface of activated T cells.

PD-1 is found on activated T cells, B cells and monocytes, with some low expression on natural killer T (NKT) cells and also has two B7 family ligands, PD-L1 and PD-L2. PD-L1 is expressed on B cells, T cells, (including regulatory T cells), myeloid cells, dendritic cells, and endothelial cells. It can also be found in some non-lymphoid organs like lung, heart, muscle, pancreas and placenta.

ICOS is present on T cells and can be upregulated following activation of both TCR and CD28. It is also expressed on activated NK cells. The single ligand for ICOS is the ICOS ligand (ICOSL) that is found on B cells, macrophages, dendritic cells, some T cells, and some endothelial and epithelial cells.