(cluster of differentiation
4) is a glycoprotein
expressed on the surface of T helper cells
, regulatory T cells
, and dendritic cells
. It was discovered in the late 1970s and was originally known as leu-3 and T4 (after the OKT4 monoclonal antibody that reacted with it) before being named CD4 in 1984.
On T cells
, CD4 is a co-receptor
that assists the T cell receptor
(TCR) to activate its T cell following an interaction with an antigen presenting cell
. 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
Like many cell surface receptors/markers, CD4 is a member of the immunoglobulin superfamily.
It has four immunoglobulin domains (D1 to D4) that are exposed on the extracellular surface of the cell:
- D1 and D3 resemble immunoglobulin variable (IgV) domains.
- D2 and D4 resemble immunoglobulin constant (IgC) domains.
CD4 uses its D1 domain to interact with the β2-domain of MHC class II molecules. T cells expressing CD4 molecules (and not CD8) on their surface, therefore, are specific for antigens presented by MHC II and not by MHC class I (they are MHC class II-restricted).
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 above.
Role in HIV infection
CD4 is also a primary receptor used by HIV-1 to gain entry into host T cells.
The HIV-1 virus attaches to CD4 with a particular protein in its viral envelope known as gp120. The binding to CD4 creates a shift in the conformation of the viral gp120 protein allowing HIV-1 to bind to two other cell surface receptors on the host cell (the chemokine receptors CCR5 or CXCR4, depending on whether HIV is infecting a macrophage or T-helper cell, respectively). Following another change in shape of a different viral protein (gp41), HIV inserts a fusion peptide into the host T cell that allows the outer membrane of the virus to fuse with the T-cell membrane.
HIV infection leads to a progressive reduction in the number of T cells possessing CD4 receptors and, therefore, the CD4 count is used as an indicator to help physicians and clinicians decide when to begin treatment in HIV-infected patients. Normal blood values are > 1 x109/L.
Role in HIV treatments
CD4 tests consist in enumerating the number of T cells containing the CD4 receptor. Results are usually expressed in cell per microliter of blood. While CD4 tests are not an HIV test (they do not look for the presence of viral DNA, or for the presence of specific Antibodies) CD4 tests are critical in assessing the immune system of patients. Treatments are often started when the CD4 count reach a low point, around ~200 cells per microliter. CD4 tests are also used to judge treatment efficacy.