CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells. They are called helper cells because one of their main roles is to send signals to other types of immune cells, including CD8 killer cells, which then destroy the infectious particle. If CD4 cells become depleted, for example in untreated HIV infection, or following immune suppression prior to a transplant, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight.
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). MHC class I contains Beta-2 microglobulin.
CD4 is a co-receptor that assists the T cell receptor (TCR) in communicating with an antigen-presenting cell. Using its intracellular domain, CD4 amplifies the signal generated by the TCR by recruiting an enzyme, the tyrosine kinaseLck, which is essential for activating many molecular components of the signaling cascade of an activated T cell. Various types of T helper cells are thereby produced. CD4 also interacts directly with MHC class II molecules on the surface of the antigen-presenting cell using its extracellular domain. The extracellular domain adopts an immunoglobulin-like beta-sandwich with seven strands in 2 beta sheets, in a Greek key topology.
HIV-1 uses CD4 to gain entry into host T-cells and achieves this through its viral envelope protein known as gp120. The binding to CD4 creates a shift in the conformation of gp120 allowing HIV-1 to bind to a co-receptor expressed on the host cell. These co-receptors are chemokine receptorsCCR5 or CXCR4. 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 expressing CD4. Medical professionals refer to the CD4 count to decide when to begin treatment during HIV infection. Normal blood values are usually expressed as the number of cells per microliter (or cubic millimeter, mm3) of blood, with normal values for CD4 cells being 500-1200 cells/mm3. A CD4 count measures the number of T cells expressing CD4. While CD4 counts are not a direct HIV test--e.g. they do not check the presence of viral DNA, or specific antibodies against HIV--they are used to assess the immune system of a patient. Patients often undergo treatments when the CD4 counts reach a level of 350 cells per microliter in Europe but usually around 500cpm in the US; people with less than 200 cells per microliter are at high risk of contracting AIDS defined illnesses. The newest National Institute of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count Medical professionals also refer to CD4 tests to determine efficacy of treatment.
^Bernard A, Boumsell L, Hill C (1984). "Joint Report of the First International Workshop on Human Leucocyte Differentiation Antigens by the Investigators of the Participating Laboratories". In Bernard A, Boumsell L, Dausset J, Milstein C, Schlossman SF. Leucocyte typing: human leucocyte differentiation antigens detected by monoclonal antibodies: specification, classification, nomenclature. Berlin: Springer. pp. pages 45–48. doi:10.1007/978-3-642-68857-7_3. ISBN0-387-12056-4. Report on the first international references workshop sponsored by INSERM, WHO and IUIS
^Brady R, Dodson E, Dodson G, Lange G, Davis S, Williams A et al. (May 1993). "Crystal structure of domains 3 and 4 of rat CD4: relation to the NH2-terminal domains". Science260 (5110): 979–83. doi:10.1126/science.8493535. PMID8493535.
^Rudd C, Trevillyan J, Dasgupta J, Wong L, Schlossman S (September 2010). "Pillars article: the CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. 1988". J. Immunol.185 (5): 2645–9. PMID20724730.
^Hawash I, Hu X, Adal A, Cassady J, Geahlen R, Harrison M (April 2002). "The oxygen-substituted palmitic acid analogue, 13-oxypalmitic acid, inhibits Lck localization to lipid rafts and T cell signaling". Biochim. Biophys. Acta1589 (2): 140–50. doi:10.1016/S0167-4889(02)00165-9. PMID12007789.
^Kwong P, Wyatt R, Robinson J, Sweet R, Sodroski J, Hendrickson W (June 1998). "Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody". Nature393 (6686): 648–59. doi:10.1038/31405. PMID9641677.
^Kumarasen Cooper; Anthony S-Y. Leong (2003). Manual of diagnostic antibodies for immunohistology. London: Greenwich Medical Media. p. 65. ISBN1-84110-100-1.
^Zamani M, Tabatabaiefar M, Mosayyebi S, Mashaghi A, Mansouri P (July 2010). "Possible association of the CD4 gene polymorphism with vitiligo in an Iranian population". Clin. Exp. Dermatol.35 (5): 521–4. doi:10.1111/j.1365-2230.2009.03667.x. PMID19843086.
Greenway A, Holloway G, McPhee D, Ellis P, Cornall A, Lidman M (2004). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". J. Biosci.28 (3): 323–35. doi:10.1007/BF02970151. PMID12734410.
Bénichou S, Benmerah A (2003). "[The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway]". Med Sci (Paris)19 (1): 100–6. doi:10.1051/medsci/2003191100. PMID12836198.
Leavitt S, SchOn A, Klein J, Manjappara U, Chaiken I, Freire E (2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Curr. Protein Pept. Sci.5 (1): 1–8. doi:10.2174/1389203043486955. PMID14965316.
Hout D, Mulcahy E, Pacyniak E, Gomez L, Gomez M, Stephens E (2005). "Vpu: a multifunctional protein that enhances the pathogenesis of human immunodeficiency virus type 1". Curr. HIV Res.2 (3): 255–70. doi:10.2174/1570162043351246. PMID15279589.
Li L, Li H, Pauza C, Bukrinsky M, Zhao R (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Res.15 (11–12): 923–34. doi:10.1038/sj.cr.7290370. PMID16354571.