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 CD8killer 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.
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.
The immunoglobulin variable (IgV) domain of D1 adopts an immunoglobulin-like β-sandwich fold with seven β-strands in two β-sheets, in a Greek key topology.[8]
CD4 interacts with the β2-domain of MHC class II molecules through its D1 domain. T cells displaying 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.[citation needed]
CD4 is a co-receptor of the T cell receptor (TCR) and assists the latter in communicating with antigen-presenting cells. The TCR complex and CD4 bind to distinct regions of the antigen-presenting MHC class II molecule. The extracellular D1 domain of CD4 binds to the β2 region of MHC class II. The resulting close proximity between the TCR complex and CD4 allows the tyrosine kinase Lck bound to the cytoplasmic tail of CD4[9] to phosphorylate tyrosine residues of immunoreceptor tyrosine activation motifs (ITAMs) on the cytoplasmic domains of CD3[10] to amplify the signal generated by the TCR. Phosphorylated ITAMs on CD3 recruit and activate SH2 domain-containing protein tyrosine kinases (PTK), such as ZAP70, to further mediate downstream signalling through tyrosine phosphorylation. These signals lead to the activation of transcription factors, including NF-κB, NFAT, AP-1, to promote T cell activation.[11]
Conservation of their respective cytoplasmic tail motifs, CxC/H in the case of CD4 and an ITIM-like motif in the case of LAG-3, supports that competition between CD4 and LAG-3 for binding of kinase LCK is a conserved core part of the jawed vertebrate immune system.
CD4 is closely related to LAG-3,[12] and together they form an evolutionary conserved system from the level of sharks competing for binding Lck by conserved motifs in their cytoplasmic tails:[13] CD4 through a Cys-X-Cys/His motif[14] and LAG-3 through an immunoreceptor tyrosine-based inhibition motif like (ITIM-like) motif.[13][15][16] LAG-3, which is an inhibitory receptor, is upregulated in activated T cells as a kind of negative feedback loop.
HIV-1 uses CD4 to gain entry into host T-cells and achieves this through its viral envelope protein known as gp120.[19] 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 pathology
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, although recent medical guidelines have changed to recommend treatment at all CD4 counts as soon as HIV is diagnosed. 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.[citation needed]
National Institutes of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count[20] Normal blood values are usually expressed as the number of cells per microliter (μL, or equivalently, cubic millimeter, mm3) of blood, with normal values for CD4 cells being 500–1200 cells/mm3.[21] Patients often undergo treatments when the CD4 counts reach a level of 350 cells per microliter in Europe but usually around 500/μL in the US; people with less than 200 cells per microliter are at high risk of contracting AIDS defined illnesses. Medical professionals also refer to CD4 tests to determine efficacy of treatment.[citation needed]
Viral load testing provides more information about the efficacy for therapy than CD4 counts.[22] For the first 2 years of HIV therapy, CD4 counts may be done every 3–6 months.[22] If a patient's viral load becomes undetectable after 2 years then CD4 counts might not be needed if they are consistently above 500/mm3.[22] If the count remains at 300–500/mm3, then the tests can be done annually.[22] It is not necessary to schedule CD4 counts with viral load tests and the two should be done independently when each is indicated.[22]
T-cells play a large part in autoinflammatory diseases.[25] When testing a drug's efficacy or studying diseases, it is helpful to quantify the amount of T-cells
on fresh-frozen tissue with CD4+, CD8+, and CD3+ T-cell markers (which stain different markers on a T-cell – giving different results).[26]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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 (eds.). Leucocyte typing: human leucocyte differentiation antigens detected by monoclonal antibodies: specification, classification, nomenclature. Berlin: Springer. pp. 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 RL, Dodson EJ, Dodson GG, Lange G, Davis SJ, Williams AF, Barclay AN (May 1993). "Crystal structure of domains 3 and 4 of rat CD4: relation to the NH2-terminal domains". Science. 260 (5110): 979–983. Bibcode:1993Sci...260..979B. doi:10.1126/science.8493535. PMID8493535.
^Ohashi K, Takizawa F, Tokumaru N, Nakayasu C, Toda H, Fischer U, et al. (August 2010). "A molecule in teleost fish, related with human MHC-encoded G6F, has a cytoplasmic tail with ITAM and marks the surface of thrombocytes and in some fishes also of erythrocytes". Immunogenetics. 62 (8): 543–559. doi:10.1007/s00251-010-0460-1. PMID20614118. S2CID12282281.
^Cooper K, Leong AS (2003). Manual of diagnostic antibodies for immunohistology. London: Greenwich Medical Media. p. 65. ISBN1-84110-100-1.
^Zamani M, Tabatabaiefar MA, Mosayyebi S, Mashaghi A, Mansouri P (July 2010). "Possible association of the CD4 gene polymorphism with vitiligo in an Iranian population". Clinical and Experimental Dermatology. 35 (5): 521–524. doi:10.1111/j.1365-2230.2009.03667.x. PMID19843086. S2CID10427963.
Leavitt SA, SchOn A, Klein JC, Manjappara U, Chaiken IM, Freire E (February 2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Current Protein & Peptide Science. 5 (1): 1–8. doi:10.2174/1389203043486955. PMID14965316.
Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (April 2004). "HIV/SIV escape from immune surveillance: focus on Nef". Current HIV Research. 2 (2): 141–151. doi:10.2174/1570162043484924. PMID15078178.
Hout DR, Mulcahy ER, Pacyniak E, Gomez LM, Gomez ML, Stephens EB (July 2004). "Vpu: a multifunctional protein that enhances the pathogenesis of human immunodeficiency virus type 1". Current HIV Research. 2 (3): 255–270. doi:10.2174/1570162043351246. PMID15279589.
Joseph AM, Kumar M, Mitra D (January 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID15638726.
