Immunoglobulin superfamily: Wikis


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Immunoglobulin domains of three distinct members of the immunoglobulin superfamily. Each domain is distinguished within a colored circle

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, certain cytokine receptors and intracellular muscle proteins. They are commonly associated with roles in the immune system.


Immunoglobulin domains

Proteins of the IgSF possess a structural domain known as an immunoglobulin (Ig) domain. Ig domains are named after the immunoglobulin molecules. They contain about 70-110 amino acids and are categorized according to their size and function.[1] Ig-domains possess a characteristic Ig-fold, which has a sandwich-like structure formed by two sheets of antiparallel beta strands. Interactions between hydrophobic amino acids on the inner side of the sandwich and a highly conserved disulfide bonds formed between cysteine residues in the B and F strands, stabilize the Ig-fold. One end of the Ig domain has a section called the complementarity determining region that is important for the specificity of antibodies for their ligands.

Most Ig domains are either variable (IgV) or constant (IgC). IgV domains with 9 beta strands are generally longer than IgC domains with 7 beta strands. Ig domains of some members of the IgSF resemble IgV domains in the amino acid sequence, 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 (I) domains.[2]

Members of the immunoglobulin superfamily

Members of the immunoglobulin superfamily
Molecule function/category Examples
Antigen receptors
Antigen presenting molecules
Antigen receptor accessory molecules
Co-stimulatory or inhibitory molecules
  • CD28
  • CD80 and CD86 (also known as B7.1 and B7.2 molecules)
Receptors on Natural killer cells
Adhesion molecules
Cytokine and growth factor receptors
Receptor tyrosine kinases/phosphatases
Ig binding receptors
  • CD147
  • Thymocyte differentiation antigen-1 (Thy-1), also known as CD90
  • CD7
  • Butyrophilins (Btn)
  • Sodium channel subunit beta-1 precursor
  • Titin a huge intracellular muscle protein

The Ig domain was reported to be the most populous family of proteins in the human genome with 765 members identified.[3] Members of the family can be found even in the bodies of animals with a simple physiological structure such as poriferan sponges. They have also been found in bacteria which presumably moved inside the microorganisms through horizontal gene transfer.[4]


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);[5] 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).[6]

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.[7] 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.[8] CTLA-4 is expressed on the surface of activated T cells.[5]

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.[9]

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.[10]


  1. ^ Barclay A (2003). "Membrane proteins with immunoglobulin-like domains--a master superfamily of interaction molecules". Semin Immunol 15 (4): 215–23. doi:10.1016/S1044-5323(03)00047-2. PMID 14690046.  
  2. ^ Harpaz Y, Chothia C (May 1994). "Many of the immunoglobulin superfamily domains in cell adhesion molecules and surface receptors belong to a new structural set which is close to that containing variable domains". J. Mol. Biol. 238 (4): 528–39. doi:10.1006/jmbi.1994.1312. PMID 8176743.  
  3. ^ Lander ES, Linton LM, Birren B, et al. (February 2001). "Initial sequencing and analysis of the human genome". Nature 409 (6822): 860–921. doi:10.1038/35057062. PMID 11237011.  
  4. ^ Bateman A, Eddy SR, Chothia C (September 1996). "Members of the immunoglobulin superfamily in bacteria". Protein Sci. 5 (9): 1939–41. doi:10.1002/pro.5560050923. PMID 8880921. PMC 2143528.  
  5. ^ a b Peggs K, Allison J (2005). "Co-stimulatory pathways in lymphocyte regulation: the immunoglobulin superfamily". Br J Haematol 130 (6): 809–24. doi:10.1111/j.1365-2141.2005.05627.x. PMID 16156851.  
  6. ^ Greenwald R, Freeman G, Sharpe A (2005). "The B7 family revisited". Annu Rev Immunol 23: 515–48. doi:10.1146/annurev.immunol.23.021704.115611. PMID 15771580.  
  7. ^ Borriello F, Sethna MP, Boyd SD, Schweitzer AN, Tivol EA, Jacoby D, Strom TB, Simpson EM, Freeman GJ, Sharpe AH (1997). "B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation". Immunity 6 (3): 303–13. doi:10.1016/S1074-7613(00)80333-7. PMID 16156851.  
  8. ^ Bhatia S, Edidin M, Almo S, Nathenson S (2006). "B7-1 and B7-2: similar costimulatory ligands with different biochemical, oligomeric and signaling properties". Immunol Lett 104 (1-2): 70–5. doi:10.1016/j.imlet.2005.11.019. PMID 16413062.  
  9. ^ Greenwald R, Freeman G, Sharpe A (2005). "The B7 family revisited". Annu Rev Immunol 23: 515–48. doi:10.1146/annurev.immunol.23.021704.115611. PMID 15771580.  
  10. ^ Nurieva RI, Mai XM, Forbush K, Bevan MJ, Dong C (2003). "B7h is required for T cell activation, differentiation, and effector function". Proc Natl Acad Sci USA 100 (24): 14163–8. doi:10.1073/pnas.2335041100. PMID 14615582.  

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