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CD4

From Wikipedia, the free encyclopedia

For other uses, see CD-4 (disambiguation).
CD4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD4, CD4mut, CD4 molecule, OKT4D, IMD79
External IDsOMIM: 186940; MGI: 88335; HomoloGene: 513; GeneCards: CD4; OMA:CD4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

920

12504

Ensembl

ENSG00000010610

ENSMUSG00000023274

UniProt

P01730

P06332

RefSeq (mRNA)

NM_013488

RefSeq (protein)

NP_038516

Location (UCSC)Chr 12: 6.79 – 6.82 MbChr 6: 124.84 – 124.87 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
CD4, Cluster of differentiation 4, extracellular
structure of T cell surface glycoprotein cd4, monoclinic crystal form
Identifiers
SymbolCD4-extrcel
PfamPF09191
InterProIPR015274
SCOP21cid / SCOPe / SUPFAM
OPM superfamily193
OPM protein2klu
CDDcd07695
Membranome27
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Image of CD4 co-receptor binding to MHC (Major Histocompatibility Complex) non-polymorphic region.

In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, 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.[5] In humans, the CD4 protein is encoded by the CD4 gene.[6][7]

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.

YouTube Encyclopedic

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  • How HIV kills so many CD4 T cells | Infectious diseases | NCLEX-RN | Khan Academy
  • Co-receptors CD4 and CD8 (FL-Immuno/29)
  • Review of B cells, CD4+ T cells and CD8+ T cells | NCLEX-RN | Khan Academy
  • Part 4 - HIV and the Skin - HIV Dermatoses Resistant to CD4 Count Recovery
  • How HIV infects us: CD4 (T-helper) lymphocyte infection | NCLEX-RN | Khan Academy

Transcription

- [Voiceover] We know that in an untreated HIV infection, the levels of the virus rise up. They rise up to extremely high levels throughout our bloodstream and throughout our body. And that's because HIV is getting into our immune cells, right? They hijack our T cells and they use them to replicate and to make lots and lots of copies of themselves. But we also know that we see this massive drop off in our T cells, our CD4 cells in particular. So the question is, how is this happening? I mean, yeah, we see that these cells get infected, but why are so many of them dying? Do they all get infected, do they die when they get infected? Well, this question is one that scientists have been working on for decades, probably about 30 years so far. And it turns out that in an HIV infection, only about 5-10% of the immune cells that end up dying off are actually HIV infected. The remaining 90-95% that die off are not even infected. That's ridiculous, right? How's that even possible? Well, let's look at that a little bit. So why all these cells, both infected and non-infected are dying, it really comes down to a few causes. And we could talk about all the molecular detail involved in each of these causes, but I don't really want us to get bogged down in all the detail. So let's just focus on the concepts here. So here's an infected T cell, right? This guy's part of the 5-10% that dies off while infected. So here's our T cell. And inside our T cell you can see there's little bits of HIV RNA, and you can see new HIV particles budding off on the outside here, right? This guy's just cranking out more and more HIV particles. And actually, let's just put a bit of a red-colored haze around the edges here. And that's to remind ourselves that a lot of the infected cells die off while they're still traveling around in our blood stream. So this is just to show us where this is happening. So infected CD4 T cells, they're gonna die off either directly because of stuff the virus is doing within the infected cell, within themself, or because of how our immune system responds to them. Our immune systems don't particularly like when our cells get infected, and that's fair enough. But let's start down here, virus-related stuff. Remember that when a virus gets its RNA into our immune cell, this cell is considered to be infected at that point. So from here, our cell can die off in a few different ways. So first off, if HIV comes in and starts reverse transcribing, remember it works by reverse transcriptase, right? If it starts to reverse transcribe lots and lots of copies of viral DNA using its RNA, our cell might start to take notice. We start to notice these viral transcripts building up. And we actually have a specific protein in our cells called IFI16, and it's IFI16's job to be on the lookout for all this rogue DNA, DNA that really shouldn't be in our cells. So if IFI16 does take notice of all these viral transcripts building up, it activates an inflammatory cascade within the cell. And what ends up happening with this is the inflammatory cascade goes on to activate a self-destruct sequence within the cell, and we call this pyroptosis. Basically, the cell self-destructs because of the really, really, inflammatory environment inside the cell. And that's called pyroptosis. And keep this in mind, because this pyroptosis mechanism gets really, really important later on in the video, so keep that in mind. The second way an infected T cell might die off, do you remember integrase, that's the HIV enzyme that will grab on to this viral DNA here, drag it into the nucleus, and then try to integrate it into our DNA? Well, sometimes while integrase is getting its integration on, our cell sort of catches on to what's happening, so to speak. And our cell catches on because we have another cellular sensor called DNA-PK that senses when there's a break in our DNA. So at this point, our sensor's triggered, right? And then our cell's like, holy cow! We have an HIV infection! And it goes on to, again, trigger a self-destruct sequence. Except this one's slightly different to the one we saw earlier. This one's called apoptosis, which you may or may not have heard of in your cell biology class. Now apoptosis and pyroptosis are pretty similar, but they primarily differ in how they get triggered. Remember pyroptosis is triggered by inflammation, but apoptosis is triggered when specific cellular watchdogs, if you will, notice some critical damage happening in the cell, like the DNA damage we saw here. And finally another thing that might happen, is that let's say integrase actually does get the job done, and the viral DNA ends up integrated into our DNA. At that point we might start cranking out copies of virus, right? And remember that one of the last steps in creating viable HIV virus is that this viral protein, HIV protease, has to cleave up the viral precursors that have been made in our cell in order to activate 'em and to make 'em all "infectiousy." So what happens, I guess as a byproduct of that, is that the HIV protease also will cleave up and activate other proteins in our cell called caspases. Specifically a fragment of caspase number 8. There's lots of different kinds of caspases, but this one activates number 8. And caspases are pretty cool. Often when there's a problem within the cell, like there is right now, the caspases get activated and they trigger, you guessed it, a self-destruct sequence, in this case apoptosis again. So there are other ways that infected T cells can die, too. For example we've got another group of T cells called CD8 T cells. And when they see an infected CD4 cell, they get pretty upset, and they'll kill it off. And the reason it knows the CD4 cell's infected, by the way, is because infected CD4 cells start to display certain HIV proteins on their surface. For example, maybe they'll start to display ones from the HIV envelope, like GP120. Another thing to keep in mind is that remember after a month or so of being infected, we start to make antibodies to HIV? So these anti HIV antibodies might stick on to infected T cells and mark them for destruction by other immune cells. So everything we've talked about so far are really just concepts about how infected CD4 cells die. But like I mentioned earlier, it's been observed that a massive amount of immune cell loss in an HIV infection, actually the vast majority, is due to the death of CD4 T cells that are not even infected. And this loss of uninfected T cells is so huge that it's thought to be the major reason for immune system failure in an advanced HIV infection. Part of why there's such a huge loss of these uninfected cells is because when T cells get exposed to HIV, even if they don't get infected by it, they start to produce this protein on their surface that causes them to hone in on our lymph nodes. They start to travel to our lymph nodes. And the reason for this is, because, remember, the lymph nodes are the areas in our immune system where our immune cells go to get exposed to new types of bacteria and other bugs that they're supposed to be fighting, right? They're kinda like training grounds for our immune cells. So we know that lymph nodes are just this massive hotbed for HIV particles in an infection, right? Remember, that's part of why we see the swollen glands and the raised lymph nodes in acute HIV infections. Because dendritic cells are bringing HIV to lymph nodes and immune responses start to happen there. So anyway, you end up with this really large amount of uninfected T cells all within your lymph nodes. And actually, let me draw in this creamy-colored haze here. So that reminds us that all of this cell death is gonna primarily happen within our lymph tissue. So what happens in here is pyroptosis again. Remember it's programmed cell death, like apoptosis, but initiated by a different mechanism. It's driven by this crazy amount of inflammation. So let me set the scene for you here. So you get HIV trying to infect a CD4 T cell in here, right? But remember that IFI16 protein we talked about earlier. That protein notices all of these viral transcripts building up, right? And when it notices that, it activates a caspase, caspase 1 this time. And caspase 1 does something really, really interesting. It starts to stimulate the creation of this pro-inflammatory molecule called interleukin-1 beta inside our cell. And interleukin-1 beta, what it does, is it creates this really inflammatory environment inside the cell. And remember what happens when you have a massively inflammatory environment in the cell? The cell might end up being destroyed by pyroptosis. And, indeed, that's exactly what happens here. You can actually think of it like a grenade going off. And I think we all know that grenades suck, because of shrapnel that they release that causes damage to bystanders. And in fact, there is a similar thing that happens here. So the shrapnel after pyroptosis are all of these little pro-inflammatory interleukin-1 beta particles that then get exposed to all the other CD4 cells around the area, right? All the cells that have come in to try to control the HIV infection. So when they get showered in interleukin-1 beta, they start to develop a seriously inflammatory environment inside themselves as well. So what ultimately happens is that they undergo pyroptosis as well. And you get this chain reaction of pyroptosing cells creating this huge loss of CD4 cells that weren't even infected in the first place. The other thing is that you end up with this state of chronic inflammation, right? All throughout your body. And that's because of all these pro-inflammatory signals that are being released. And this chronic inflammation that develops keeps activating your immune cells, essentially 24/7. And that'll eventually wear out your immune cells and lead to even more cell death. So before, we used to think that we lost the majority of our CD4 cells because of HIV infecting each cell, leading to apoptosis of that one cell. But now we know that it's this ridiculous amount of pyroptosis and the resulting chain reactions of more and more and more pyroptosis that it causes that's responsible for the vast majority of CD4 cell loss in HIV infection.

Structure

Schematic representation of CD4 receptor.

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:

The immunoglobulin variable (IgV) domain of D1 adopts an immunoglobulin-like β-sandwich fold with seven β-strands in 2 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.

The short cytoplasmic/intracellular tail (C) of CD4 contains a special sequence of amino acids that allow it to recruit and interact with the tyrosine kinase Lck.

Function

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.

Other interactions

CD4 has also been shown to interact with SPG21,[17] and Uncoordinated-119 (Unc-119).[18]

Disease

HIV infection

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 receptors CCR5 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]

Reference ranges for blood tests of white blood cells, comparing CD4+ cell amount (shown in green-yellow) with other cells.

Other diseases

CD4 continues to be expressed in most neoplasms derived from T helper cells. It is therefore possible to use CD4 immunohistochemistry on tissue biopsy samples to identify most forms of peripheral T cell lymphoma and related malignant conditions.[23] The antigen has also been associated with a number of autoimmune diseases such as vitiligo and type I diabetes mellitus.[24]

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]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000010610 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023274 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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. ISBN 0-387-12056-4. Report on the first international references workshop sponsored by INSERM, WHO and IUIS
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  13. ^ a b Takizawa F, Hashimoto K, Miyazawa R, Ohta Y, Veríssimo A, Flajnik MF, et al. (2023-12-21). "CD4 and LAG-3 from sharks to humans: related molecules with motifs for opposing functions". Frontiers in Immunology. 14: 1267743. doi:10.3389/fimmu.2023.1267743. PMC 10768021. PMID 38187381.
  14. ^ Kim PW, Sun ZY, Blacklow SC, Wagner G, Eck MJ (September 2003). "A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8". Science. 301 (5640): 1725–1728. Bibcode:2003Sci...301.1725K. doi:10.1126/science.1085643. PMID 14500983. S2CID 32336829.
  15. ^ 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. PMID 20614118. S2CID 12282281.
  16. ^ Maeda TK, Sugiura D, Okazaki IM, Maruhashi T, Okazaki T (April 2019). "Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation". The Journal of Biological Chemistry. 294 (15): 6017–6026. doi:10.1074/jbc.RA119.007455. PMC 6463702. PMID 30760527.
  17. ^ Zeitlmann L, Sirim P, Kremmer E, Kolanus W (March 2001). "Cloning of ACP33 as a novel intracellular ligand of CD4". The Journal of Biological Chemistry. 276 (12): 9123–9132. doi:10.1074/jbc.M009270200. PMID 11113139.
  18. ^ Gorska MM, Stafford SJ, Cen O, Sur S, Alam R (February 2004). "Unc119, a novel activator of Lck/Fyn, is essential for T cell activation". The Journal of Experimental Medicine. 199 (3): 369–379. doi:10.1084/jem.20030589. PMC 2211793. PMID 14757743.
  19. ^ Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA (June 1998). "Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody". Nature. 393 (6686): 648–659. Bibcode:1998Natur.393..648K. doi:10.1038/31405. PMC 5629912. PMID 9641677.
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  22. ^ a b c d e HIV Medicine Association (February 2016), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, HIV Medicine Association, retrieved 9 May 2016
  23. ^ Cooper K, Leong AS (2003). Manual of diagnostic antibodies for immunohistology. London: Greenwich Medical Media. p. 65. ISBN 1-84110-100-1.
  24. ^ 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. PMID 19843086. S2CID 10427963.
  25. ^ Ciccarelli F, De Martinis M, Ginaldi L (2014). "An update on autoinflammatory diseases". Current Medicinal Chemistry. 21 (3): 261–269. doi:10.2174/09298673113206660303. PMC 3905709. PMID 24164192.
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Further reading

External links

This article incorporates text from the public domain Pfam and InterPro: IPR015274
This page was last edited on 3 June 2024, at 07:34
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