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Definition

CD4 is a glycoprotein expressed on T cells, monocytes, macrophages and dendritic cells1.  CD4 peptides are peptides derived from CD4 sequence that are used mainly to study its functions1.

 

Discovery

CD4 was first identified in peripheral lymphocytes by genomic blotting techniques in 19862.

 

Classification

CD4 is a glycoprotein that belongs to the immunoglobulin superfamily of proteins2.

 

Structural Characteristics

CD4 has four immunoglobulin domains (D1 to D4) that are exposed on the extracellular surface of the cell: D1 and D3 resemble immunoglobulin variable (IgV) domains3. D2 and D4 resemble immunoglobulin constant (IgC) domains3. CD4 uses its D1 domain to interact with the ß2-domain of MHC class II molecules3. The short cytoplasmic/intracellular tail (C) of CD4 contains a special sequence of amino acids that allow it to interact with the lck molecule described above3.

 

Mode of action

CD4+ T cells are initially activated when an antigen presenting cells presents an antigen bound to MHC molecule4.  CD4 bound to MHC in turn activates several kinases that allow the activation of CD4 and CD3 through phosphorylation4.  Activated CD4 and other molecules trigger several signals in the cytosol that form the first step in T cell activation4.

 

Functions

CD4 is a co-receptor that assists the T cell receptor to activate its T cell following an interaction with an antigen presenting cell5. Using its portion that resides inside the T cell, CD4 amplifies the signal generated by the TCR by recruiting an enzyme, known as the tyrosine kinase lck, which is essential for activating many molecules involved in the signaling cascade of an activated T cell. CD4 also interacts directly with MHC class II molecules on the surface of the antigen presenting cell using its extracellular domain5.

 

CD4 is a primary receptor used by HIV-1 to gain entry into host T cells. HIV-1 attaches to CD4 with a protein in its viral envelope known as gp120 allowing HIV-1 to bind to two other surface receptors on the host cells, CCR5 or CXCR46.  Following a structural change in another viral protein (gp41), HIV inserts a fusion peptide into the host cell that allows the outer membrane of the virus to fuse with the cell membrane.  HIV infection leads to a progressive reduction in the number of T cells possessing CD4 receptors6.

 

 

References

 

1.     Zhou L, Chong MM, Littman DR (2009). Plasticity of CD4+ T cell lineage differentiation. Immunity, 30(5), 646-55.

2.     Isobe M, Huebner K, Maddont PJ, Littmant DL, Axelt R and Croce CM (1986). The gene encoding the T-cell surface protein T4 is located on human chromosome 12 (T4 glycoprotein/chromosome mapping/acquired immunodeficiency syndrome receptor/in situ hybridization/T lymphocytes. Proc. Natl. Acad. Sci. USA, 83, 4399-4402.

3.     Ryu SE, Truneh A, Sweet RW, Hendrickson WA (1994). Structures of an HIV and MHC binding fragment from human CD4 as refined in two crystal lattices. Structure, 2 (1): 59–74.

4.     Miceli MC, Parnes JR (1993). Role of CD4 and CD8 in T cell activation and differentiation. Adv. Immunol., 53: 59–122.

5.     Harrington, LE; RD Hatton & PR Mangan (2005). Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunology, 6 (11), 1023-32.

6.     Anderson JL, Hope TJ (2005). HIV accessory proteins and surviving the host cell. Current HIV/AIDS reports, 1 (1), 47–53.

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