CD16: Difference between revisions
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'''CD16''' is a | '''CD16,''' also known as FcγRIII, is a [[cluster of differentiation]] molecule found on the surface of [[natural killer cell]]s, [[neutrophil]] polymorphonuclear leukocytes, [[monocytes]] and [[macrophages]].<ref>{{cite book | last = Janeway | first = Charles | name-list-format = vanc | title = Immunobiology | publisher = Garland | location = New York | year = 2001 | isbn = 0-8153-3642-X | edition = 5 | chapter = Appendix II. CD antigens}}</ref> CD16 has been identified as Fc receptors [[FcγRIIIa]] (CD16a) and [[FcγRIIIb]] (CD16b), which participate in signal transduction.<ref>{{cite journal | vauthors = Vivier E, Morin P, O'Brien C, Druker B, Schlossman SF, Anderson P | title = 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 = Journal of Immunology | volume = 146 | issue = 1 | pages = 206–10 | date = January 1991 | pmid = 1701792 }}</ref> 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 cell-mediated cytotoxicity|antibody-dependent cellular cytotoxicity]] (ADCC).<ref name="Mandelboim_1999">{{cite journal | vauthors = Mandelboim O, Malik P, Davis DM, Jo CH, Boyson JE, Strominger JL | title = Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 10 | pages = 5640–4 | date = May 1999 | pmid = 10318937 | pmc = 21913 }}</ref> 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. | ||
== Function == | |||
CD16 is the type III [[Neonatal Fc receptor|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.<ref name = "Zhang_2000" /> While FcγRIIIa is expressed on mast cells, macrophages, and natural killer cells as a transmembrane receptor, FcγRIIIb is only expressed on neutrophils.<ref name="Zhang_2000" /> 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 [[Respiratory burst|oxidative burst]], which allows neutrophils to clear opsonized pathogens.<ref name="Zhang_2000" /> | |||
== | == 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.<ref name="Yeap_2016" /> 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.<ref name="Yeap_2016">{{cite journal | vauthors = Yeap WH, Wong KL, Shimasaki N, Teo EC, Quek JK, Yong HX, Diong CP, Bertoletti A, Linn YC, Wong SC | title = CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes | language = En | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 34310 | date = September 2016 | pmid = 27670158 | doi = 10.1038/srep34310 }}</ref> In addition, CD16 is able to mediate the direct killing of some virally infected and cancer cells without antibodies.<ref name="Mandelboim_1999" /> | |||
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.<ref>{{cite journal | vauthors = Anegón I, Cuturi MC, Trinchieri G, Perussia B | title = 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 | journal = The Journal of Experimental Medicine | volume = 167 | issue = 2 | pages = 452–72 | date = February 1988 | pmid = 2831292 | doi = 10.1084/jem.167.2.452 | url = http://jem.rupress.org/content/167/2/452 }}</ref> This CD16-induced expression of cytokine mRNA in NK cells is mediated by the nuclear factor of activated T cells (NFATp), a [[Ciclosporin|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.<ref>{{cite journal | vauthors = Aramburu J, Azzoni L, Rao A, Perussia B | title = Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding | journal = The Journal of Experimental Medicine | volume = 182 | issue = 3 | pages = 801–10 | date = September 1995 | pmid = 7650486 | doi = 10.1084/jem.182.3.801 | url = http://jem.rupress.org/content/182/3/801 | pmc = 2192167 }}</ref> | |||
== Structure == | |||
The crystal structures of FcεRIα, FcγRIIa, FcγRIIb and FcγRIII have been experimentally determined. These structures revealed a conserved immunoglobulin-like (Ig-like) structure.<ref name="Garman_1998">{{cite journal | vauthors = Garman SC, Kinet JP, Jardetzky TS | title = Crystal structure of the human high-affinity IgE receptor | journal = Cell | volume = 95 | issue = 7 | pages = 951–61 | date = December 1998 | pmid = 9875849 | doi = 10.1016/S0092-8674(00)81719-5 }}</ref> 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°.<ref name="Zhang_2000">{{cite journal | vauthors = Zhang Y, Boesen CC, Radaev S, Brooks AG, Fridman WH, Sautes-Fridman C, Sun PD | title = Crystal structure of the extracellular domain of a human FcγRIII | journal = Immunity | volume = 13 | issue = 3 | pages = 387–95 | date = September 2000 | pmid = 11021536 | doi = 10.1016/S1074-7613(00)00038-8 }}</ref> The receptor’s Fc binding region also carries a net positive charge, which complements the negatively-charged receptor binding regions on Fc.<ref name="Zhang_2000" /> | |||
== 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.<ref name="Goodier_2016">{{cite journal | vauthors = Goodier MR, Lusa C, Sherratt S, Rodriguez-Galan A, Behrens R, Riley EM | title = Sustained Immune Complex-Mediated Reduction in CD16 Expression after Vaccination Regulates NK Cell Function | language = English | journal = Frontiers in Immunology | volume = 7 | pages = 384 | date = 2016 | pmid = 27725819 | doi = 10.3389/fimmu.2016.00384 | url = https://www.frontiersin.org/articles/10.3389/fimmu.2016.00384/full }}</ref> 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.<ref name="Goodier_2016" /> | |||
CD16 is often used as an additional marker to reliably identify different subsets of human immune cells.<ref name="Pillay_2013">{{cite journal | vauthors = Pillay J, Tak T, Kamp VM, Koenderman L | title = Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences | journal = Cellular and Molecular Life Sciences | volume = 70 | issue = 20 | pages = 3813–27 | date = October 2013 | pmid = 23423530 | pmc = 3781313 | doi = 10.1007/s00018-013-1286-4 }}</ref> Several other CD molecules, such as CD11b and CD33, are traditionally used as markers for human myeloid-derived suppressor cells (MDSCs).<ref name="Pillay_2013" /> 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.<ref>{{cite journal | vauthors = Dumitru CA, Moses K, Trellakis S, Lang S, Brandau S | title = Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology | journal = Cancer Immunology, Immunotherapy | volume = 61 | issue = 8 | pages = 1155–67 | date = August 2012 | pmid = 22692756 | doi = 10.1007/s00262-012-1294-5 }}</ref> 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.<ref>{{cite journal | vauthors = Elghetany MT | title = Surface antigen changes during normal neutrophilic development: a critical review | journal = Blood Cells, Molecules & Diseases | volume = 28 | issue = 2 | pages = 260–74 | date = March 2002 | pmid = 12064921 }}</ref> | |||
==As a drug target== | ==As a drug target== | ||
[[Margetuximab]] targets CD16A in preference to CD16B.<ref>{{cite web|title=Margetuximab|url=http://adisinsight.springer.com/drugs/800022516|website=AdisInsight| | With its expression on neutrophils, CD16 represents a possible target in cancer immunotherapy. [[Margetuximab]], an Fc-optimized monoclonal antibody that recognizes the [[HER2/neu|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.<ref>{{cite web | title = Margetuximab | url = http://adisinsight.springer.com/drugs/800022516 | website = AdisInsight | access-date = 1 February 2017 }}</ref> In addition, CD16 could play a role in antibody-targeting cancer therapies. Bispecific antibody fragments, such as anti-[[CD19]]/CD16, allow the targeting of immunotherapeutic drugs to the cancer cell. Anti-CD19/CD16 [[Single-chain variable fragment|diabodies]] have been shown to enhance the natural killer cell response to B-cell [[Lymphoma|lymphomas]].<ref>{{cite journal | vauthors = Schrama D, Reisfeld RA, Becker JC | title = Antibody targeted drugs as cancer therapeutics | journal = Nature Reviews. Drug Discovery | volume = 5 | issue = 2 | pages = 147-59 | date = February 2006 | pmid = 16424916 | doi = 10.1038/nrd1957 }}</ref> Furthermore, targeting extrinsic factors such as [[Fas ligand|FasL]] or [[TRAIL]] to the tumor cell surface triggers death receptors, inducing apoptosis by both autocrine and paracrine processes. | ||
==References== | == References == | ||
{{Reflist}} | {{Reflist|32em}} | ||
==External links== | == External links == | ||
* {{MeshName|CD16+Antigens}} | * {{MeshName|CD16+Antigens}} | ||
| Line 61: | Line 72: | ||
[[Category:Clusters of differentiation]] | [[Category:Clusters of differentiation]] | ||
[[Category:Fc receptors]] | [[Category:Fc receptors]] | ||
Latest revision as of 22:46, 15 May 2018
| Fc fragment of IgG, low affinity IIIa, receptor (CD16a) | |
|---|---|
| Identifiers | |
| Symbol | FCGR3A |
| Alt. symbols | FCGR3, FCG3 |
| Entrez | 2214 |
| HUGO | 3619 |
| OMIM | 146740 |
| RefSeq | NM_000569 |
| UniProt | P08637 |
| Other data | |
| Locus | Chr. 1 q23 |
| Fc fragment of IgG, low affinity IIIb, receptor (CD16b) | |
|---|---|
| Identifiers | |
| Symbol | FCGR3B |
| Alt. symbols | FCGR3, FCG3 |
| Entrez | 2215 |
| HUGO | 3620 |
| OMIM | 610665 |
| RefSeq | NM_000570 |
| UniProt | O75015 |
| Other data | |
| Locus | Chr. 1 q23 |
CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophil polymorphonuclear leukocytes, monocytes and macrophages.[1] CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction.[2] 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).[3] 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.
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.[4] While FcγRIIIa is expressed on mast cells, macrophages, and natural killer cells as a transmembrane receptor, FcγRIIIb is only expressed on neutrophils.[4] 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.[4]
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.[5] 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.[5] In addition, CD16 is able to mediate the direct killing of some virally infected and cancer cells without antibodies.[3]
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.[6] 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.[7]
Structure
The crystal structures of FcεRIα, FcγRIIa, FcγRIIb and FcγRIII have been experimentally determined. These structures revealed a conserved immunoglobulin-like (Ig-like) structure.[8] 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°.[4] The receptor’s Fc binding region also carries a net positive charge, which complements the negatively-charged receptor binding regions on Fc.[4]
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.[9] 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.[9]
CD16 is often used as an additional marker to reliably identify different subsets of human immune cells.[10] Several other CD molecules, such as CD11b and CD33, are traditionally used as markers for human myeloid-derived suppressor cells (MDSCs).[10] 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.[11] 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.[12]
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.[13] In addition, CD16 could play a role in antibody-targeting cancer therapies. 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.[14] 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.
References
- ↑ Janeway C (2001). "Appendix II. CD antigens". Immunobiology (5 ed.). New York: Garland. ISBN 0-8153-3642-X.
- ↑ 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. PMID 1701792.
- ↑ 3.0 3.1 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. PMC 21913. PMID 10318937.
- ↑ 4.0 4.1 4.2 4.3 4.4 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.
- ↑ 5.0 5.1 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. doi:10.1038/srep34310. PMID 27670158.
- ↑ 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. PMID 2831292.
- ↑ 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.
- ↑ 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.
- ↑ 9.0 9.1 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. PMID 27725819.
- ↑ 10.0 10.1 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.
- ↑ 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.
- ↑ Elghetany MT (March 2002). "Surface antigen changes during normal neutrophilic development: a critical review". Blood Cells, Molecules & Diseases. 28 (2): 260–74. PMID 12064921.
- ↑ "Margetuximab". AdisInsight. Retrieved 1 February 2017.
- ↑ 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.
External links
- CD16+Antigens at the US National Library of Medicine Medical Subject Headings (MeSH)