Immunoglobulin Superfamily

The immunoglobulin superfamily (IgSF) is the most abundant gene/protein family in the human genome with 765 members identified. All IgSF members share a structural domain known as the immunoglobulin (Ig)-like domain, which is named after the immunoglobulin or antibody molecules. Antibodies are specialized proteins that recognize foreign antigens, such as bacteria and viruses, as part of the body's immune response. Antibodies contain a variable (V) region and a constant (C) region. Ig-like domains can resemble either the variable (V) region or the constant (C) region; these domains are referred to as Ig V-set/-type (IgV) and C-set/-type (IgC), respectively (see the structure below). Some Ig-like domains have characteristics of both IgV and IgC; these domains are described as Ig I-set/-type (IgI), meaning intermediate.

The Ig-like domains normally contain 70-110 amino acids and are characterized by an Ig fold, a sandwich-like structure formed by two sheets of antiparallel β-strands (see the structure above). Interactions between hydrophobic amino acids on the inner side of the sandwich and highly conserved disulfide bonds between two sheets stabilize the Ig-fold. The Ig-like domains can be further classified according to their size and function. For example, the IgV domains (right) typically contain 9 β-strands that are longer than IgC domains that have only 7 β-strands (left). On one side of the IgV domain, there is a section termed the complementarity determining regions (CDR1-3) that are critical for the specificity of an antibody or IgV domain binding to the ligand. Some Ig-like domains resemble IgV in the amino acid sequence, but are similar in size to IgC domains. They are termed IgC₂ domains, whereas standard IgC domains are referred to as IgC₁ domains.

Much like the role of antibodies to recognize particular antigens, the Ig-like domains allow proteins to interact with other molecules (see the diagram and examples below). Many IgSF members are cell surface or soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. They include cell surface antigen receptors, co-receptors, co-inhibitory and co-stimulatory molecules for the immune system. Some IgSF members are molecules involved in antigen presentation to lymphocytes, cell adhesion molecules (CAMs), and cytokine receptors. They are commonly associated with functional roles in our immune system. Interestingly many IgI domain containing proteins act as receptors for growth factors, stimulating signaling inside the cell that helps respond to its environment. Other IgI domain containing proteins are also found in muscle cells; their ability to bind other muscle proteins aid in muscle contraction. Due to the diverse functions, changes in many IgSF members at genetic or proteomic levels can cause a variety of disorders that affect different body systems.

Examples of IgSF Members

Molecule Category	Examples	Description
Antigen receptors	• Antibodies or IgM • T cell receptor chains	Immunoglobulins or antibodies (the antigen receptors of B cells) are the founding members of the IgSF. In humans, there are 5 distinct types of Ig molecule all containing a heavy chain with 4-5 Ig domains and a light chain with 2 Ig domains. The antigen receptor of T cells is the T cell receptor (TCR), which is composed of two chains, either the TCRα and TCRβ chains, or the TCRδ γ and TCRγ chains. All TCR chains contain 2 Ig domains (IgV-IgC) in their extracellular regions.
Antigen presenting molecules	• Class I MHC • Class II MHC • β-2 microglobulin	The ligands for TCRs are major histocompatibility complex (MHC) proteins. These come in two forms; MHC class I forms a dimer with β-2 microglobulin (β2M) and interacts with the TCR on cytotoxic T cells and MHC class II has two chains (α and β) that interact with the TCR on helper T cells. MHC class I, MHC class II and β2M molecules all possess one IgC domain, respectively.
Co-receptor	• CD1 • CD4 • CD8 • CD19	Many molecules including those IgSF members on the surfaces of T cells also interact with MHC molecules during TCR engagement. These are known as co-receptors. The co-receptor CD4 is found on helper T cells and CD8 is found on cytotoxic T cells. Like CD1, CD8 has only 1 IgV domain but exists as a dimeric molecule (CD8α/32k and CD8β/37k). The co-receptor CD4 contains 4 IgV domains and exists as a monomeric molecule. A co-receptor complex is also used by the B cell receptor (BCR), including CD19 with 2 IgC₂-domains.
Antigen receptor accessory molecules	• CD3-γ, -δ and -ε • CD79a and CD79b	CD3 is a molecule that helps to transmit a signal from the TCR following its interaction with MHC molecules. 3 different chains γ, -δ and -ε contain a single IgV domain. B cells also have cell surface accessory molecules, CD79a and CD79b. They contain a single IgV domain and assist with cell activation through BCR.
Co-stimulatory or inhibitory molecules	• CD28 • B7-1/CD80 and B7-2/CD86 • CTLA4 • PD1 • PD-L1 and PD-L2	One major group of co-stimulatory and inhibitory receptors are members of the CD28 family receptors, including CD28, CTLA4/CD152, 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, including CD80 (B7-1), CD86 (B7-2), ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x).
Cell adhesion molecules (CAMs)	• NCAMs • ICAMs • CD2 subset	CD2 subset of IgSF represented a large group of homologous cell adhesion molecules (CAMs), includes CD2, CD58, CD48, CD150, CD229 and CD244.
Cytokine or growth factor receptors	• IL6R • CSF1R • PDGFR • SCFR/c-Kit/CD117	Interleukin-6 receptorColony and stimulating factor 1 receptor; Platelet-derived growth factor receptor (PDGFR) and Mast/stem cell growth factor receptor precursor (SCFR, c-kit, CD117 antigen)
Receptor tyrosine kinases or phosphatases	• Tie1/Tie2 • RPTPs	Tyrosine-protein kinase receptor Tie1/Tie2 precursor; Type IIa and Type IIb Receptor protein tyrosine phosphatases (RPTPs), including, but not limited to PTPRM, PTPRK, PTPRU, PTPRD, PTPRF