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The CD4 (T4) Molecule

The D1 and D2 domains of CD4

So you want to know about CD4?

Co-Receptor Function
Role in HIV infection

What is CD4?

CD4 is a glycoprotein found on the surfaces of thymocytes and mature T lymphocytes, as well as macrophages, Langerhans cells, neuronal cells, glial cells, and some virus-transformed B-cells (Sekaly and Rooke, 1998).   It has also been found on sperm (Lavitrano et al., 1997).  CD4 was originally discovered and used as a marker for helper T-cells until further investigation demonstrated that it actually plays a role in recognition of antigen and activation of the cell (Janeway et al., 1999).  CD4 functions primarily as a coreceptor for the T-cell receptor, decreasing the amount of antigen required for cell activation, but it can also bind antigen independent of the T-cell receptor (Miceli et al., 1991).  Work with HIV has shown that CD4 plays a major HIV receptor role.

What is the shape and size of CD4?

The 55 kDa CD4 molecule has four extracellular subunits, named D1-D4, that total 397 amino acids, a transmembrane region of 23 amino acids, and a cytoplasmic tail with 38 amino acids.  The N-terminal domain, D1, is the furthest from the membrane.  It is comprised mostly of an Ig-like beta barrel with nine beta strands.  Its last strand is connected immediately to the first strand of D2, making the D1-D2 fragment rigid.  This part of the molecule is connected by a hinge region to the D3-D4 section, which also consists of two domains rigidly connected.  The cytoplasmic tail contains three serine residues that may be available for phosphorylation (Sekaly and Rooke, 1998).  The src-family protein tyrosine kinase p56lck is bound to the cytoplasmic tail, allowing CD4 to function in signal transduction (Miceli et al., 1991).

How is CD4 encoded in DNA?

The 33 kb CD4 gene is located on chromosome 12 in humans and comprises ten exons.  The D1 region is encoded in two exons, and each of D2, D3, D4, and the transmembrane region have their own single exon.  The cytoplasmic tail is encoded in one exon and part of a second (Pigot and Power, 1993).  The full CD4 transcipt is 3.7 kb, but a shorter, 2.7 kb transcript has been detected in human brain tissue.  The truncation appears to affect the cytoplasmic tail, but its function is unclear (Sekaly and Rooke, 1998).

How does CD4 help the TCR?

CD4 serves as a coreceptor for the T-cell receptor on helper T-cells.  CD4 reduces by 100-fold the amount of antigen required to stimulate a T-cell response to antigen (Janeway et al., 1999).  Like an immunoglobulin, CD4 has three complementarity determining loops on its D1 domain.  It is thought that CDR-1, CDR-2, and CDR-3, plus a loop on D2 named FG, all bind to an MHC class II molecule.  The site of this binding is not the face of the MHC-II, where the TCR concurrently associates, but to highly conserved regions in the alpha2 and beta2 domains of MHC-II.  An interaction is thought to be stabilized by the dimerization of CD4 through contact in the D4 region (Huang et al., 1997).  The association of CD4 to MHC-II during antigen recognition increases the activity of p56lck (Veilette et al., 1989).  The exact mechanism for this is not completely clear, but it is thought that association with MHC-II brings the CD4 and its associated p56lck within close proximity of its substrates, including the ZAP-70 protein kinase.  Phosphorylation of ZAP-70 by the lck serves to amplify the signal received by the TCR, thus allowing the signal transduction cascade to activate the T-cell to begin secreting cytokines (Janeway et al., 1999).

What else can CD4 do?

In addition to its function as a co-receptor, CD4 has co-ligand activity.  It is able, through a smaller range of contact sites, to bind antigen directly (Huang et al., 1997).  One example of this is its role in HIV infection.  The viral gp120 of HIV binds to amino acids 40-60 of the D1 domain of CD4 (Sekaly and Rooke, 1998).

A complex of the CD4 molecule, HIV gp120,
and an immunoglobulin.

Because of this, and the fact that monoclonal antibodies blocking the CD4 binding site protects a cell against HIV infection, it is known that CD4 plays a crucial role in the infection of a cell by HIV (McClure and Dalgleish, 1998).  Though other coreceptors are thought to be involved in cellular HIV-infection, the current knowledge of the CD4 pathway may be helpful in the prevention and treatment of HIV infection.


References and Further Reading

Cammarota, G, Schierle, A, Takacs, B, Doran, DM, Knorr, R, Bannwarth, W, Guardiola, J, Sinigaglia, F. Identification of aCD4 binding site on the  domain of HLA-DR molecules.  Nature 1992 30 April;356:799-801.

Friedman, TM, Reddy, AP, Wassell, R, Jameson, BA, Korngold, R.  Identification of a Human CD4-CDR3-like Surface Involved in CD4+ T Cell Function.  J Biol Chem 1996 13 September;271(37):22635-40.

Huang, B, Yachou, A, Fleury, S, Hendrickson, W, Sekaly, RP.  Analysis of the Contact Sites on the CD4 Molecule with Class II MHC Molecule.  J Immunol. 1997 1 January;158(1):216-25.

Janeway, CA, Travers, P, Walprt, M, Capra, JD.  1999.  Immunobiology:  The Immune System in Health and Disease, 4th ed.  New York:  Current Biology Publications, Elsevier Science.  p 155-157, 174-175.

Lifson, JD, Reyes, GR, McGrath, MS, Stein, BS, Engleman, EG.  AIDS Retrovirus Induced Cytopathology:  Giant Cell Formation and Involvement of CD4 Antigen.  Science 1986 30 May;232:1123-7.

McClure, M, Dalgleish, A.  1998.  Human Immunodeficiency Virus.  In:  Delves, PJ, Roit, IM, editors.  Encyclopedia of Immunology, vol 1.  Academic Press, Harcourt Brace and Company Publishers.  p 1130-1141.

Miceli, MC, von Hoegen, P, Parnes, JR.  Adhesion versus coreceptor function of CD4 and CD8:  Role of the cytoplasmic tail in coreceptor activity.  Proc Natl Acad Sci USA  1991 April;88:2623-27.

Parham, P.  The Box and the Rod.  Nature 1992 18 June;357:538-9.

Riberdy, JM, Mostaghel, E, Doyle, C.  Disruption of the CD4-major histocompatibility complex class II interaction blocks the development of CD4+ T cells in vivo.  Proc Natl Acad Sci USA  1998 April;95:4493-8.

Sekaly, RP, Rooke R.  1998.  CD4. In:  Delves, PJ, Roit, IM, editors.  Encyclopedia of Immunology, vol 2.  Academic Press, Harcourt Brace and Company Publishers. p 468-471.

Veillette, A, Bookman, MA, Horak, EM, Samelson, LE, Bolen, JB.  Signal transduction through the CD4 receptro invoves the activation of the internal membrae tyrosine-protein kinase p56lck.  Nature 1989 16 March;338:257-9.

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