CD16

Last updated • 5 min readFrom Wikipedia, The Free Encyclopedia
Fc fragment of IgG, low affinity IIIa, receptor (CD16a)
Identifiers
Symbol FCGR3A
Alt. symbolsFCGR3, FCG3
NCBI gene 2214
HGNC 3619
OMIM 146740
RefSeq NM_000569
UniProt P08637
Other data
Locus Chr. 1 q23
Search for
Structures Swiss-model
Domains InterPro
Fc fragment of IgG, low affinity IIIb, receptor (CD16b)
Identifiers
Symbol FCGR3B
Alt. symbolsFCGR3, FCG3
NCBI gene 2215
HGNC 3620
OMIM 610665
RefSeq NM_000570
UniProt O75015
Other data
Locus Chr. 1 q23
Search for
Structures Swiss-model
Domains InterPro

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. [1] [2] CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. [3] The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). [4] It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

Contents

Function

CD16 is the type III Fcγ receptor. In humans, it exists in two different forms: FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which have 96% sequence similarity in the extracellular immunoglobulin binding regions. [5] While FcγRIIIa is expressed on mast cells, macrophages, and natural killer cells as a transmembrane receptor, FcγRIIIb is only expressed on neutrophils. [5] In addition, FcγRIIIb is the only Fc receptor anchored to the cell membrane by a glycosyl-phosphatidylinositol (GPI) linker, and also plays a significant role in triggering calcium mobilization and neutrophil degranulation. FcγRIIIa and FcγRIIIb together are able to activate degranulation, phagocytosis, and oxidative burst, which allows neutrophils to clear opsonized pathogens. [5]

Mechanism and regulation

These receptors bind to the Fc portion of IgG antibodies, which then activates antibody-dependent cell-mediated cytotoxicity (ADCC) in human NK cells. CD16 is required for ADCC processes carried out by human monocytes. [6] In humans, monocytes expressing CD16 have a variety of ADCC capabilities in the presence of specific antibodies, and can kill primary leukemic cells, cancer cell lines, and cells infected with hepatitis B virus. [6] In addition, CD16 is able to mediate the direct killing of some virally infected and cancer cells without antibodies. [4]

After binding to ligands such as the conserved section of IgG antibodies, CD16 on human NK cells induce gene transcription of surface activation molecules such as IL-2-R (CD25) and inflammatory cytokines such as IFN-gamma and TNF. [7] This CD16-induced expression of cytokine mRNA in NK cells is mediated by the nuclear factor of activated T cells (NFATp), a cyclosporin A (CsA)-sensitive factor that regulates the transcription of various cytokines. The upregulated expression of specific cytokine genes occurs via a CsA-sensitive and calcium-dependent mechanism. [8]

Structure

The crystal structures of FcεRIα, FcγRIIa, FcγRIIb and FcγRIII have been experimentally determined. These structures revealed a conserved immunoglobulin-like (Ig-like) structure. [9] In addition, the structures demonstrated a common feature in all known Ig superfamily Fc receptors: the acute hinge angle between the N- and C-terminal Ig domains. Specifically, the structure of CD16 (FcγRIIIb) consists of two immunoglobulin-like domains, with an interdomain hinge angle of around 50°. [5] The receptor's Fc binding region also carries a net positive charge, which complements the negatively-charged receptor binding regions on Fc. [5]

Clinical significance

CD16 plays a significant role in early activation of natural killer (NK) cells following vaccination. In addition, CD16 downregulation represents a possible way to moderate NK cell responses and maintain immune homeostasis in both T cell and antibody-dependent signaling pathways. [10] In a normal, healthy individual, cross-linking of CD16 (FcγRIII) by immune complexes induces antibody-dependent cellular cytotoxicity (ADCC) in NK cells. However, this pathway can also be targeted in cancerous or diseased cells by immunotherapy. After influenza vaccination, CD16 downregulation was associated with significant upregulation of influenza-specific plasma antibodies, and positively correlated with degranulation of NK cells. [10]

CD38 on leukocytes attaching to CD16 on endothelial cells allows for leukocyte binding to blood vessel walls, and the passage of leukocytes through blood vessel walls. [11]

CD16 is often used as an additional marker to reliably identify different subsets of human immune cells. [12] Several other CD molecules, such as CD11b and CD33, are traditionally used as markers for human myeloid-derived suppressor cells (MDSCs). [12] However, since these markers are also expressed on NK cells and all other cells derived from myelocytes, other markers are required, such as CD14 and CD15. Neutrophils are found to be CD14low and CD15high, whereas monocytes are CD14high and CD15low. [13] While these two markers are sufficient to differentiate between neutrophils and monocytes, eosinophils have a similar CD15 expression to neutrophils. Therefore, CD16 is used as a further marker to identify neutrophils: mature neutrophils are CD16high, while eosinophils and monocytes are both CD16low. CD16 allows for distinction between these two types of granulocytes. Additionally, CD16 expression varies between the different stages of neutrophil development: neutrophil progenitors that have differentiation capacity are CD16low, with increasing expression of CD16 in metamyelocytes, banded, and mature neutrophils, respectively. [14]

CD16-positive T cells have been found in patients with chronic viral infections [15] [16] or after organ transplantation [17] as well as in patients with severe COVID-19. [2] CD16 expression enables antibody-mediated degranulation and thus allows T cell receptor-independent cytotoxicity. In patients with severe COVID-19, CD16-positive T cells may lead to exacerbated cytotoxicity, promote microvascular endothelial cell injury and contribute to disease severity. [2]

As a drug target

With its expression on neutrophils, CD16 represents a possible target in cancer immunotherapy. Margetuximab, an Fc-optimized monoclonal antibody that recognizes the human epidermal growth factor receptor 2 (HER2) expressed on tumor cells in breast, bladder, and other solid tumor cancers, targets CD16A in preference to CD16B. [18] In addition, CD16 could play a role in antibody-targeting cancer therapies. FcγRIV, a murine homologue of CD16A has been shown to be involved in antibody-mediated depletion of tumor-infiltrating regulatory T cells in monoclonal antibody mediated immunotherapy. [19] Bispecific antibody fragments, such as anti-CD19/CD16, allow the targeting of immunotherapeutic drugs to the cancer cell. Anti-CD19/CD16 diabodies have been shown to enhance the natural killer cell response to B-cell lymphomas. [20] Furthermore, targeting extrinsic factors such as FasL or TRAIL to the tumor cell surface triggers death receptors, inducing apoptosis by both autocrine and paracrine processes.

Related Research Articles

<span class="mw-page-title-main">Phagocytosis</span> Process by which a cell uses its plasma membrane to engulf a large particle

Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is called a phagocyte.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Most immune cells detect the antigen presented on major histocompatibility complex (MHC) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

<span class="mw-page-title-main">CD32</span> Surface receptor glycoprotein

CD32, also known as FcγRII or FCGR2, is a surface receptor glycoprotein belonging to the Ig gene superfamily. CD32 can be found on the surface of a variety of immune cells. CD32 has a low-affinity for the Fc region of IgG antibodies in monomeric form, but high affinity for IgG immune complexes. CD32 has two major functions: cellular response regulation, and the uptake of immune complexes. Cellular responses regulated by CD32 include phagocytosis, cytokine stimulation, and endocytic transport. Dysregulated CD32 is associated with different forms of autoimmunity, including systemic lupus erythematosus. In humans, there are three major CD32 subtypes: CD32A, CD32B, and CD32C. While CD32A and CD32C are involved in activating cellular responses, CD32B is inhibitory.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

<span class="mw-page-title-main">Antibody-dependent cellular cytotoxicity</span> Cell-mediated killing of other cells mediated by antibodies

Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.

<span class="mw-page-title-main">Degranulation</span> Process by which cells lose secretory granules

Degranulation is a cellular process that releases antimicrobial cytotoxic or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.

CD64 is a type of integral membrane glycoprotein known as an Fc receptor that binds monomeric IgG-type antibodies with high affinity. It is more commonly known as Fc-gamma receptor 1 (FcγRI). After binding IgG, CD64 interacts with an accessory chain known as the common γ chain, which possesses an ITAM motif that is necessary for triggering cellular activation.

<span class="mw-page-title-main">FCGR3A</span>

Low affinity immunoglobulin gamma Fc region receptor III-A is a protein that in humans is encoded by the FCGR3A gene. It is also known as CD16a as it is part of the cluster of differentiation cell surface molecules.

<span class="mw-page-title-main">FCGR2B</span>

Fc fragment of IgG receptor IIb is a low affinity inhibitory receptor for the Fc region of immunoglobulin gamma (IgG). FCGR2B participates in the phagocytosis of immune complexes and in the regulation of antibody production by B lymphocytes.

<span class="mw-page-title-main">FCAR</span> Mammalian protein found in Homo sapiens

Fc fragment of IgA receptor (FCAR) is a human gene that codes for the transmembrane receptor FcαRI, also known as CD89. FcαRI binds the heavy-chain constant region of Immunoglobulin A (IgA) antibodies. FcαRI is present on the cell surface of myeloid lineage cells, including neutrophils, monocytes, macrophages, and eosinophils, though it is notably absent from intestinal macrophages and does not appear on mast cells. FcαRI plays a role in both pro- and anti-inflammatory responses depending on the state of IgA bound. Inside-out signaling primes FcαRI in order for it to bind its ligand, while outside-in signaling caused by ligand binding depends on FcαRI association with the Fc receptor gamma chain.

<span class="mw-page-title-main">FCGR3B</span>

FCGR3B, also known as CD16b, is a human gene.

The following outline is provided as an overview of and topical guide to immunology:

Urelumab is a fully human, non‐ligand binding, CD137 agonist immunoglobulin‐γ 4 (IgG4) monoclonal antibody. It was developed utilizing Medarex's UltiMAb(R) technology by Bristol-Myers Squibb for the treatment of cancer and solid tumors. Urelumab promotes anti-tumor immunity, or an immune response against tumor cells, via CD137 activation. The application of Urelumab has been limited due to the fact that it can cause severe liver toxicity.

<span class="mw-page-title-main">Killer activation receptor</span> Class of protein

Killer Activation Receptors (KARs) are receptors expressed on the plasmatic membrane of Natural Killer cells. KARs work together with inhibitory receptors, which inactivate them in order to regulate the NK cells functions on hosted or transformed cells. These two kinds of specific receptors have some morphological features in common, such as being transmembrane proteins. The similarities are specially found in the extracellular domains and, the differences tend to be in the intracellular domains. KARs and KIRs can have tyrosine containing activatory or inhibitory motifs in the intracellular part of the receptor molecule.

The NK-92 cell line is an immortalised cell line that has the characteristics of a type of immune cell found in human blood called ’natural killer’ (NK) cells. Blood NK cells and NK-92 cells recognize and attack cancer cells as well as cells that have been infected with a virus, bacteria, or fungus. NK-92 cells were first isolated in 1992 in the laboratory of Hans Klingemann at the British Columbia Cancer Agency in Vancouver, Canada, from a patient who had a rare NK cell non-Hodgkin-lymphoma. These cells were subsequently developed into a continuously growing cell line. NK-92 cells are distinguished by their suitability for expansion to large numbers, ability to consistently kill cancer cells and testing in clinical trials. When NK-92 cells recognize a cancerous or infected cell, they secrete perforin that opens holes into the diseased cells and releases granzymes that kill the target cells. NK-92 cells are also capable of producing cytokines such as tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-y), which stimulates proliferation and activation of other immune cells.

Cytokine-induced killer cells (CIK) cells are a group of immune effector cells featuring a mixed T- and natural killer (NK) cell-like phenotype. They are generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells with interferon-gamma (IFN-γ), anti-CD3 antibody, recombinant human interleukin (IL)-1 and recombinant human interleukin (IL)-2.

<span class="mw-page-title-main">Adaptive NK cell</span> Specialized subtype of cytotoxic lymphocyte

An adaptive natural killer (NK) cell or memory-like NK cell is a specialized natural killer cell that has the potential to form immunological memory. They can be distinguished from cytotoxic NK (cNK) cells by their receptor expression profile and epigenome. Adaptive NK cells are so named for properties which they share with the adaptive immune system. Though adaptive NK cells do not possess antigen specificity, they exhibit dynamic expansions of defined cell subsets, increased proliferation and long-term persistence for up to 3 months in vivo, high IFN-γ production, potent cytotoxic activity upon ex vivo restimulation, and protective memory responses.

Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

KHYG-1 is an immortalized cell line that bears the characteristics of NK cells. NK cells are a type of immune cell that are found in blood whose innate function is to kill viral infected cells, cells under stress and cancer cells. The KHYG-1 cell line was established in 1997 in the laboratory of M Yagita in the department of Clinical Immunology and Haematology, Tazuke-Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan. These cells were derived from the blood of 45-year old female suffering from aggressive Natural killer cell lymphoblastic leukemia/lymphoma. This cell line has been growing continuously, in the presence of IL-2, for 18 months after isolation and its doubling time is around 24-48h. The ability to proliferate was retained even after cryopreservation in liquid nitrogen. 

References

  1. Janeway C (2001). "Appendix II. CD antigens" . Immunobiology (5 ed.). New York: Garland. ISBN   978-0-8153-3642-6.
  2. 1 2 3 Georg P, et al. (2021). "Complement activation induces excessive T cell cytotoxicity in severe COVID-19". Cell. 185 (3): 493–512.e25. doi:10.1016/j.cell.2021.12.040. PMC   8712270 . PMID   35032429.
  3. Vivier E, Morin P, O'Brien C, Druker B, Schlossman SF, Anderson P (January 1991). "Tyrosine phosphorylation of the Fc gamma RIII(CD16): zeta complex in human natural killer cells. Induction by antibody-dependent cytotoxicity but not by natural killing". Journal of Immunology. 146 (1): 206–10. doi: 10.4049/jimmunol.146.1.206 . PMID   1701792.
  4. 1 2 Mandelboim O, Malik P, Davis DM, Jo CH, Boyson JE, Strominger JL (May 1999). "Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity". Proceedings of the National Academy of Sciences of the United States of America. 96 (10): 5640–4. Bibcode:1999PNAS...96.5640M. doi: 10.1073/pnas.96.10.5640 . PMC   21913 . PMID   10318937.
  5. 1 2 3 4 5 Zhang Y, Boesen CC, Radaev S, Brooks AG, Fridman WH, Sautes-Fridman C, Sun PD (September 2000). "Crystal structure of the extracellular domain of a human FcγRIII". Immunity. 13 (3): 387–95. doi: 10.1016/S1074-7613(00)00038-8 . PMID   11021536.
  6. 1 2 Yeap WH, Wong KL, Shimasaki N, Teo EC, Quek JK, Yong HX, Diong CP, Bertoletti A, Linn YC, Wong SC (September 2016). "CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes". Scientific Reports. 6 (1): 34310. Bibcode:2016NatSR...634310Y. doi:10.1038/srep34310. PMC   5037471 . PMID   27670158.
  7. Anegón I, Cuturi MC, Trinchieri G, Perussia B (February 1988). "Interaction of Fc receptor (CD16) ligands induces transcription of interleukin 2 receptor (CD25) and lymphokine genes and expression of their products in human natural killer cells". The Journal of Experimental Medicine. 167 (2): 452–72. doi:10.1084/jem.167.2.452. PMC   2188858 . PMID   2831292.
  8. Aramburu J, Azzoni L, Rao A, Perussia B (September 1995). "Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding". The Journal of Experimental Medicine. 182 (3): 801–10. doi:10.1084/jem.182.3.801. PMC   2192167 . PMID   7650486.
  9. Garman SC, Kinet JP, Jardetzky TS (December 1998). "Crystal structure of the human high-affinity IgE receptor". Cell. 95 (7): 951–61. doi: 10.1016/S0092-8674(00)81719-5 . PMID   9875849. S2CID   10211658.
  10. 1 2 Goodier MR, Lusa C, Sherratt S, Rodriguez-Galan A, Behrens R, Riley EM (2016). "Sustained Immune Complex-Mediated Reduction in CD16 Expression after Vaccination Regulates NK Cell Function". Frontiers in Immunology. 7: 384. doi: 10.3389/fimmu.2016.00384 . PMC   5035824 . PMID   27725819.
  11. Quarona V, Zaccarello G, Chillemi A (2013). "CD38 and CD157: a long journey from activation markers to multifunctional molecules". Cytometry Part B . 84 (4): 207–217. doi: 10.1002/cyto.b.21092 . hdl: 2318/134656 . PMID   23576305. S2CID   205732787.
  12. 1 2 Pillay J, Tak T, Kamp VM, Koenderman L (October 2013). "Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences". Cellular and Molecular Life Sciences. 70 (20): 3813–27. doi:10.1007/s00018-013-1286-4. PMC   3781313 . PMID   23423530.
  13. Dumitru CA, Moses K, Trellakis S, Lang S, Brandau S (August 2012). "Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology". Cancer Immunology, Immunotherapy. 61 (8): 1155–67. doi:10.1007/s00262-012-1294-5. PMID   22692756. S2CID   26598520.
  14. Elghetany MT (March 2002). "Surface antigen changes during normal neutrophilic development: a critical review". Blood Cells, Molecules & Diseases. 28 (2): 260–74. doi:10.1006/bcmd.2002.0513. PMID   12064921.
  15. Björkström NK, Gonzalez VD, Malmberg KJ, Falconer K, Alaeus A, Nowak G, Jorns C, Ericzon BG, Weiland O, Sandberg JK, Ljunggren HG (2008). "Elevated numbers of Fc gamma RIIIA+ (CD16+) effector CD8 T cells with NK cell-like function in chronic hepatitis C virus infection". Journal of Immunology. 181 (6): 4219–4228. doi: 10.4049/jimmunol.181.6.4219 . PMID   18768879. S2CID   7019199.
  16. Clémenceau B, Vivien R, Debeaupuis E, Esbelin J, Biron C, Levy Y, Vié H (2011). "FcγRIIIa (CD16) induction on human T lymphocytes and CD16pos T-lymphocyte amplification". Journal of Immunotherapy. 34 (7): 542–549. doi:10.1097/CJI.0b013e31822801d4. PMID   21760529. S2CID   35442405.
  17. Jacquemont L, Tilly G, Yap M, Doan-Ngoc TM, Danger R, Guérif P, Delbos F, Martinet B, Giral M, Foucher Y, Brouard S, Degauque N (2020). "Terminally Differentiated Effector Memory CD8+ T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure". Journal of the American Society of Nephrology. 31 (4): 876–891. doi:10.1681/ASN.2019080847. PMC   7191929 . PMID   32165419.
  18. "Margetuximab". AdisInsight. Retrieved 1 February 2017.
  19. Sharma N, Vacher J, Allison JP (May 2019). "TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion". Proceedings of the National Academy of Sciences of the United States of America. 116 (21): 10453–10462. Bibcode:2019PNAS..11610453S. doi: 10.1073/pnas.1819004116 . PMC   6534983 . PMID   31076558.
  20. Schrama D, Reisfeld RA, Becker JC (February 2006). "Antibody targeted drugs as cancer therapeutics". Nature Reviews. Drug Discovery. 5 (2): 147–59. doi:10.1038/nrd1957. PMID   16424916. S2CID   15164268.