CD40 (protein): Difference between revisions

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== Function ==
== Function ==
The protein receptor encoded by this gene is a member of the [[TNF-receptor]] superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and [[germinal center]] formation.<ref>{{cite journal|last1=Grewal|first1=IS|last2=Flavell|first2=RA|title=CD40 and CD154 in cell-mediated immunity|journal=Annual Review of Immunology|date=1998|volume=16|pages=111–35|doi=10.1146/annurev.immunol.16.1.111|pmid=9597126}}</ref> [[AT-hook]] transcription factor [[AKNA]] is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The TNFR-receptor associated factor adaptor proteins [[TRAF1]], [[TRAF2]], [[TRAF6]] and possibly [[TRAF5]] interact with this receptor serve as mediators of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.<ref>{{cite web | title = Entrez Gene: CD40 CD40 molecule, TNF receptor superfamily member 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=958| accessdate = }}</ref>
The protein receptor encoded by this gene is a member of the [[TNF-receptor]] superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and [[germinal center]] formation.<ref>{{cite journal | vauthors = Grewal IS, Flavell RA | title = CD40 and CD154 in cell-mediated immunity | journal = Annual Review of Immunology | volume = 16 | pages = 111–35 | date = 1998 | pmid = 9597126 | doi = 10.1146/annurev.immunol.16.1.111 }}</ref> [[AT-hook]] transcription factor [[AKNA]] is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The TNFR-receptor associated factor adaptor proteins [[TRAF1]], [[TRAF2]], [[TRAF6]] and possibly [[TRAF5]] interact with this receptor serve as mediators of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.<ref>{{cite web | title = Entrez Gene: CD40 CD40 molecule, TNF receptor superfamily member 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=958| access-date = }}</ref>


== Specific effects on cells ==
== Specific effects on cells ==
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The [[B cell]] can present [[antigens]] to [[helper T cell]]s. If an activated [[T cell]] recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40 receptor, causing B cell activation. The T cell also produces [[Interleukin-2|IL-2]], which directly influences B cells. As a result of this net stimulation, the B cell can undergo division, [[antibody]] [[isotype switching]], and differentiation to [[plasma cell]]s. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target.
The [[B cell]] can present [[antigens]] to [[helper T cell]]s. If an activated [[T cell]] recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40 receptor, causing B cell activation. The T cell also produces [[Interleukin-2|IL-2]], which directly influences B cells. As a result of this net stimulation, the B cell can undergo division, [[antibody]] [[isotype switching]], and differentiation to [[plasma cell]]s. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target.
Early evidence for these effects were that in CD40 or CD154 deficient mice, there is little [[class switching]] or [[germinal centre]] formation,<ref>{{cite journal|last1=Kawabe et al|first1=T|title=The immune response in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation|journal=Immunity|date=1994-06-01|volume=1|issue=3|pages=167–78|doi=10.1016/1074-7613(94)90095-7}}</ref> and immune responses are severely inhibited.
Early evidence for these effects were that in CD40 or CD154 deficient mice, there is little [[class switching]] or [[germinal centre]] formation,<ref name="KawabeNaka1994">{{cite journal | vauthors = Kawabe T, Naka T, Yoshida K, Tanaka T, Fujiwara H, Suematsu S, Yoshida N, Kishimoto T, Kikutani H | title = The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation | journal = Immunity | volume = 1 | issue = 3 | pages = 167–78 | date = June 1994 | pmid = 7534202 | doi = 10.1016/1074-7613(94)90095-7 }}</ref> and immune responses are severely inhibited.


The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including [[dendritic cells]], [[B cells]] and [[macrophages]]. It can also be expressed by [[endothelial cells]], [[smooth muscle cells]], fibroblasts and epithelial cells.<ref>{{cite journal | vauthors = Chatzigeorgiou A, Lyberi M, Chatzilymperis G, Nezos A, Kamper E | title = CD40/CD40L signaling and its implication in health and disease | journal = BioFactors (Oxford, England) | volume = 35 | issue = 6 | pages = 474–83 | year = 2009 | pmid = 19904719 | doi = 10.1002/biof.62 }}</ref> Consistent with its widespread expression on normal cells, CD40 is also expressed on a wide range of tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, [[myeloma]] and some [[carcinomas]] including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD154 interactions may play a role in the control of B cell [[haematopoiesis]].<ref>{{cite journal | vauthors = Carlring J, Altaher HM, Clark S, Chen X, Latimer SL, Jenner T, Buckle AM, Heath AW | title = CD154-CD40 interactions in the control of murine B cell hematopoiesis | journal = Journal of Leukocyte Biology | volume = 89 | issue = 5 | pages = 697–706 | date = May 2011 | pmid = 21330346 | doi = 10.1189/jlb.0310179 | pmc=3382295}}</ref>
The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including [[dendritic cells]], [[B cells]] and [[macrophages]]. It can also be expressed by [[endothelial cells]], [[smooth muscle cells]], fibroblasts and epithelial cells.<ref>{{cite journal | vauthors = Chatzigeorgiou A, Lyberi M, Chatzilymperis G, Nezos A, Kamper E | title = CD40/CD40L signaling and its implication in health and disease | journal = BioFactors | volume = 35 | issue = 6 | pages = 474–83 | year = 2009 | pmid = 19904719 | doi = 10.1002/biof.62 }}</ref> Consistent with its widespread expression on normal cells, CD40 is also expressed on a wide range of tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, [[myeloma]] and some [[carcinomas]] including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD154 interactions may play a role in the control of B cell [[haematopoiesis]].<ref>{{cite journal | vauthors = Carlring J, Altaher HM, Clark S, Chen X, Latimer SL, Jenner T, Buckle AM, Heath AW | title = CD154-CD40 interactions in the control of murine B cell hematopoiesis | journal = Journal of Leukocyte Biology | volume = 89 | issue = 5 | pages = 697–706 | date = May 2011 | pmid = 21330346 | pmc = 3382295 | doi = 10.1189/jlb.0310179 }}</ref>


== Interactions ==
== Interactions ==


CD40 (protein) has been shown to [[Protein-protein interaction|interact]] with [[TRAF2]],<ref name=pmid10411888>{{cite journal | vauthors = McWhirter SM, Pullen SS, Holton JM, Crute JJ, Kehry MR, Alber T | title = Crystallographic analysis of CD40 recognition and signaling by human TRAF2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 15 | pages = 8408–13 | date = Jul 1999 | pmid = 10411888 | pmc = 17529 | doi = 10.1073/pnas.96.15.8408 }}</ref><ref name=pmid9990007>{{cite journal | vauthors = Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J | title = Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 4 | pages = 1234–9 | date = Feb 1999 | pmid = 9990007 | pmc = 15446 | doi = 10.1073/pnas.96.4.1234 }}</ref><ref name=pmid9020361>{{cite journal | vauthors = Malinin NL, Boldin MP, Kovalenko AV, Wallach D | title = MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1 | journal = Nature | volume = 385 | issue = 6616 | pages = 540–4 | date = Feb 1997 | pmid = 9020361 | doi = 10.1038/385540a0 }}</ref> [[TRAF3]],<ref name=pmid9990007/><ref name=pmid7527023>{{cite journal | vauthors = Hu HM, O'Rourke K, Boguski MS, Dixit VM | title = A novel RING finger protein interacts with the cytoplasmic domain of CD40 | journal = The Journal of Biological Chemistry | volume = 269 | issue = 48 | pages = 30069–72 | date = Dec 1994 | pmid = 7527023 }}</ref><ref name=pmid10984535>{{cite journal | vauthors = Ni CZ, Welsh K, Leo E, Chiou CK, Wu H, Reed JC, Ely KR | title = Molecular basis for CD40 signaling mediated by TRAF3 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 19 | pages = 10395–9 | date = Sep 2000 | pmid = 10984535 | pmc = 27035 | doi = 10.1073/pnas.97.19.10395 }}</ref><ref name=pmid9384571>{{cite journal | vauthors = Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC | title = The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases | journal = The EMBO Journal | volume = 16 | issue = 23 | pages = 6914–25 | date = Dec 1997 | pmid = 9384571 | pmc = 1170295 | doi = 10.1093/emboj/16.23.6914 }}</ref> [[TRAF6]],<ref name=pmid9990007/><ref name=pmid9384571/> [[TRAF5]]<ref name=pmid9990007/><ref name=pmid8790348>{{cite journal | vauthors = Ishida TK, Tojo T, Aoki T, Kobayashi N, Ohishi T, Watanabe T, Yamamoto T, Inoue J | title = TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 18 | pages = 9437–42 | date = Sep 1996 | pmid = 8790348 | pmc = 38446 | doi = 10.1073/pnas.93.18.9437 }}</ref> and [[TTRAP]].<ref name=pmid10764746>{{cite journal | vauthors = Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten JG, Dewulf N, de Boer M, Vandenabeele P, Huylebroeck D, Remacle JE | title = TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation | journal = The Journal of Biological Chemistry | volume = 275 | issue = 24 | pages = 18586–93 | date = Jun 2000 | pmid = 10764746 | doi = 10.1074/jbc.M000531200 }}</ref>
CD40 (protein) has been shown to [[Protein-protein interaction|interact]] with [[TRAF2]],<ref name=pmid10411888>{{cite journal | vauthors = McWhirter SM, Pullen SS, Holton JM, Crute JJ, Kehry MR, Alber T | title = Crystallographic analysis of CD40 recognition and signaling by human TRAF2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 15 | pages = 8408–13 | date = July 1999 | pmid = 10411888 | pmc = 17529 | doi = 10.1073/pnas.96.15.8408 }}</ref><ref name=pmid9990007>{{cite journal | vauthors = Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J | title = Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 4 | pages = 1234–9 | date = February 1999 | pmid = 9990007 | pmc = 15446 | doi = 10.1073/pnas.96.4.1234 }}</ref><ref name=pmid9020361>{{cite journal | vauthors = Malinin NL, Boldin MP, Kovalenko AV, Wallach D | title = MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1 | journal = Nature | volume = 385 | issue = 6616 | pages = 540–4 | date = February 1997 | pmid = 9020361 | doi = 10.1038/385540a0 }}</ref> [[TRAF3]],<ref name=pmid9990007/><ref name=pmid7527023>{{cite journal | vauthors = Hu HM, O'Rourke K, Boguski MS, Dixit VM | title = A novel RING finger protein interacts with the cytoplasmic domain of CD40 | journal = The Journal of Biological Chemistry | volume = 269 | issue = 48 | pages = 30069–72 | date = December 1994 | pmid = 7527023 }}</ref><ref name=pmid10984535>{{cite journal | vauthors = Ni CZ, Welsh K, Leo E, Chiou CK, Wu H, Reed JC, Ely KR | title = Molecular basis for CD40 signaling mediated by TRAF3 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 19 | pages = 10395–9 | date = September 2000 | pmid = 10984535 | pmc = 27035 | doi = 10.1073/pnas.97.19.10395 }}</ref><ref name=pmid9384571>{{cite journal | vauthors = Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC | title = The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases | journal = The EMBO Journal | volume = 16 | issue = 23 | pages = 6914–25 | date = December 1997 | pmid = 9384571 | pmc = 1170295 | doi = 10.1093/emboj/16.23.6914 }}</ref> [[TRAF6]],<ref name=pmid9990007/><ref name=pmid9384571/> [[TRAF5]]<ref name=pmid9990007/><ref name=pmid8790348>{{cite journal | vauthors = Ishida TK, Tojo T, Aoki T, Kobayashi N, Ohishi T, Watanabe T, Yamamoto T, Inoue J | title = TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 18 | pages = 9437–42 | date = September 1996 | pmid = 8790348 | pmc = 38446 | doi = 10.1073/pnas.93.18.9437 }}</ref> and [[TTRAP]].<ref name=pmid10764746>{{cite journal | vauthors = Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten JG, Dewulf N, de Boer M, Vandenabeele P, Huylebroeck D, Remacle JE | title = TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation | journal = The Journal of Biological Chemistry | volume = 275 | issue = 24 | pages = 18586–93 | date = June 2000 | pmid = 10764746 | doi = 10.1074/jbc.M000531200 }}</ref>
 
== CD40 as a drug target in cancer ==
CD40 molecule is a potential target for [[cancer immunotherapy]]. There are number of completed and ongoing clinical trials where agonistic anti-CD40 [[Monoclonal antibody|monoclonal antibodies]] are employed to activate an anti-tumor T cell response via activation of dendritic cells.<ref>{{cite journal | vauthors = Vonderheide RH | title = The Immune Revolution: A Case for Priming, Not Checkpoint | journal = Cancer Cell | volume = 33 | issue = 4 | pages = 563–569 | date = April 2018 | pmid = 29634944 | pmc = 5898647 | doi = 10.1016/j.ccell.2018.03.008 | url = https://linkinghub.elsevier.com/retrieve/pii/S1535610818301120 }}</ref>


== References ==
== References ==
{{reflist}}
{{reflist}}


==External links==
== External links ==
* {{UCSC gene info|CD40}}
* {{UCSC gene info|CD40}}


== Further reading ==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite book  | last = Parham  | first = Peter  | title = The Immune System  | publisher = Garland Science  | edition=2nd | year = 2004  | pages = 169–173  | isbn = 0-8153-4093-1 }}
* {{cite book  | last = Parham  | first = Peter  | name-list-format = vanc | title = The Immune System  | publisher = Garland Science  | edition=2nd | year = 2004  | pages = 169–173  | isbn = 978-0-8153-4093-5 }}
* {{cite journal | vauthors = Wang JH, Zhang YW, Zhang P |title = CD40 ligand as a potential biomarker for atherosclerotic instability | journal = Neurol Res. | volume = 35 | issue = 7 | pages = 693–700 |date=September 2013 | pmid = 23561892 | doi =10.1179/1743132813Y.0000000190|display-authors=etal | pmc=3770830}}
* {{cite journal | vauthors = Wang JH, Zhang YW, Zhang P, Deng BQ, Ding S, Wang ZK, Wu T, Wang J | title = CD40 ligand as a potential biomarker for atherosclerotic instability | journal = Neurological Research | volume = 35 | issue = 7 | pages = 693–700 | date = September 2013 | pmid = 23561892 | pmc = 3770830 | doi = 10.1179/1743132813Y.0000000190 }}
* {{cite journal | vauthors = Banchereau J, Bazan F, Blanchard D, Brière F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S | title = The CD40 antigen and its ligand | journal = Annual Review of Immunology | volume = 12 | issue =  | pages = 881–922 | year = 1994 | pmid = 7516669 | doi = 10.1146/annurev.iy.12.040194.004313 }}
* {{cite journal|authorlink1=Jacques Banchereau | vauthors = Banchereau J, Bazan F, Blanchard D, Brière F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S | title = The CD40 antigen and its ligand | journal = Annual Review of Immunology | volume = 12 | issue =  | pages = 881–922 | year = 1994 | pmid = 7516669 | doi = 10.1146/annurev.iy.12.040194.004313 }}
* {{cite journal | vauthors = van Kooten C, Banchereau J | title = CD40-CD40 ligand | journal = Journal of Leukocyte Biology | volume = 67 | issue = 1 | pages = 2–17 | date = Jan 2000 | pmid = 10647992 | doi =  }}
* {{cite journal | vauthors = van Kooten C, Banchereau J | title = CD40-CD40 ligand | journal = Journal of Leukocyte Biology | volume = 67 | issue = 1 | pages = 2–17 | date = January 2000 | pmid = 10647992 | doi =  }}
* {{cite journal | vauthors = Schattner EJ | title = CD40 ligand in CLL pathogenesis and therapy | journal = Leukemia & Lymphoma | volume = 37 | issue = 5–6 | pages = 461–72 | year = 2003 | date = May 2000 | pmid = 11042507 | doi = 10.3109/10428190009058499 }}
* {{cite journal | vauthors = Schattner EJ | title = CD40 ligand in CLL pathogenesis and therapy | journal = Leukemia & Lymphoma | volume = 37 | issue = 5–6 | pages = 461–72 | date = May 2000 | pmid = 11042507 | doi = 10.3109/10428190009058499 }}
* {{cite journal | vauthors = Bhushan A, Covey LR | title = CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes | journal = Immunologic Research | volume = 24 | issue = 3 | pages = 311–24 | year = 2002 | pmid = 11817328 | doi = 10.1385/IR:24:3:311 }}
* {{cite journal | vauthors = Bhushan A, Covey LR | title = CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes | journal = Immunologic Research | volume = 24 | issue = 3 | pages = 311–24 | year = 2002 | pmid = 11817328 | doi = 10.1385/IR:24:3:311 }}
* {{cite journal | vauthors = Cheng G, Schoenberger SP | title = CD40 signaling and autoimmunity | journal = Current Directions in Autoimmunity | volume = 5 | issue =  | pages = 51–61 | year = 2002 | pmid = 11826760 | doi = 10.1159/000060547 | isbn = 3-8055-7308-1 | series = Current Directions in Autoimmunity }}
* {{Cite book | vauthors = Cheng G, Schoenberger SP | title = CD40 signaling and autoimmunity | volume = 5 | issue =  | pages = 51–61 | year = 2002 | pmid = 11826760 | doi = 10.1159/000060547 | isbn = 978-3-8055-7308-5 | series = Current Directions in Autoimmunity }}
* {{cite journal | vauthors = Dallman C, Johnson PW, Packham G | title = Differential regulation of cell survival by CD40 | journal = Apoptosis | volume = 8 | issue = 1 | pages = 45–53 | date = Jan 2003 | pmid = 12510151 | doi = 10.1023/A:1021696902187 }}
* {{cite journal | vauthors = Dallman C, Johnson PW, Packham G | title = Differential regulation of cell survival by CD40 | journal = Apoptosis | volume = 8 | issue = 1 | pages = 45–53 | date = January 2003 | pmid = 12510151 | doi = 10.1023/A:1021696902187 }}
* {{cite journal | vauthors = O'Sullivan B, Thomas R | title = Recent advances on the role of CD40 and dendritic cells in immunity and tolerance | journal = Current Opinion in Hematology | volume = 10 | issue = 4 | pages = 272–8 | year = 2004 | date = Jul 2003 | pmid = 12799532 | doi = 10.1097/00062752-200307000-00004 }}
* {{cite journal | vauthors = O'Sullivan B, Thomas R | title = Recent advances on the role of CD40 and dendritic cells in immunity and tolerance | journal = Current Opinion in Hematology | volume = 10 | issue = 4 | pages = 272–8 | date = July 2003 | pmid = 12799532 | doi = 10.1097/00062752-200307000-00004 }}
* {{cite journal | vauthors = Benveniste EN, Nguyen VT, Wesemann DR | title = Molecular regulation of CD40 gene expression in macrophages and microglia | journal = Brain, Behavior, and Immunity | volume = 18 | issue = 1 | pages = 7–12 | date = Jan 2004 | pmid = 14651941 | doi = 10.1016/j.bbi.2003.09.001 }}
* {{cite journal | vauthors = Benveniste EN, Nguyen VT, Wesemann DR | title = Molecular regulation of CD40 gene expression in macrophages and microglia | journal = Brain, Behavior, and Immunity | volume = 18 | issue = 1 | pages = 7–12 | date = January 2004 | pmid = 14651941 | doi = 10.1016/j.bbi.2003.09.001 }}
* {{cite journal | vauthors = Xu Y, Song G | title = The role of CD40-CD154 interaction in cell immunoregulation | journal = Journal of Biomedical Science | volume = 11 | issue = 4 | pages = 426–38 | year = 2005 | pmid = 15153777 | doi = 10.1159/000077892 }}
* {{cite journal | vauthors = Xu Y, Song G | title = The role of CD40-CD154 interaction in cell immunoregulation | journal = Journal of Biomedical Science | volume = 11 | issue = 4 | pages = 426–38 | year = 2005 | pmid = 15153777 | doi = 10.1159/000077892 }}
* {{cite journal | vauthors = Contin C, Couzi L, Moreau JF, Déchanet-Merville J, Merville P | title = [Immune dysfuntion of uremic patients: potential role for the soluble form of CD40] | journal = Néphrologie | volume = 25 | issue = 4 | pages = 119–26 | year = 2004 | pmid = 15291139 | doi =  }}
* {{cite journal | vauthors = Contin C, Couzi L, Moreau JF, Déchanet-Merville J, Merville P | title = [Immune dysfuntion of uremic patients: potential role for the soluble form of CD40] | journal = Nephrologie | volume = 25 | issue = 4 | pages = 119–26 | year = 2004 | pmid = 15291139 | doi =  }}
{{refend}}
{{refend}}


Revision as of 21:36, 14 December 2018

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Cluster of differentiation 40, CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Deficiency can cause Hyper-IgM syndrome type 3.

Function

The protein receptor encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation.[1] AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The TNFR-receptor associated factor adaptor proteins TRAF1, TRAF2, TRAF6 and possibly TRAF5 interact with this receptor serve as mediators of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.[2]

Specific effects on cells

In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L (CD154) on the T cell which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface which helps increase the level of activation. The increase in activation results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbe.

The B cell can present antigens to helper T cells. If an activated T cell recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40 receptor, causing B cell activation. The T cell also produces IL-2, which directly influences B cells. As a result of this net stimulation, the B cell can undergo division, antibody isotype switching, and differentiation to plasma cells. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target. Early evidence for these effects were that in CD40 or CD154 deficient mice, there is little class switching or germinal centre formation,[3] and immune responses are severely inhibited.

The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including dendritic cells, B cells and macrophages. It can also be expressed by endothelial cells, smooth muscle cells, fibroblasts and epithelial cells.[4] Consistent with its widespread expression on normal cells, CD40 is also expressed on a wide range of tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, myeloma and some carcinomas including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD154 interactions may play a role in the control of B cell haematopoiesis.[5]

Interactions

CD40 (protein) has been shown to interact with TRAF2,[6][7][8] TRAF3,[7][9][10][11] TRAF6,[7][11] TRAF5[7][12] and TTRAP.[13]

CD40 as a drug target in cancer

CD40 molecule is a potential target for cancer immunotherapy. There are number of completed and ongoing clinical trials where agonistic anti-CD40 monoclonal antibodies are employed to activate an anti-tumor T cell response via activation of dendritic cells.[14]

References

  1. ↑ Grewal IS, Flavell RA (1998). "CD40 and CD154 in cell-mediated immunity". Annual Review of Immunology. 16: 111–35. doi:10.1146/annurev.immunol.16.1.111. PMID 9597126.
  2. ↑ "Entrez Gene: CD40 CD40 molecule, TNF receptor superfamily member 5".
  3. ↑ Kawabe T, Naka T, Yoshida K, Tanaka T, Fujiwara H, Suematsu S, Yoshida N, Kishimoto T, Kikutani H (June 1994). "The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation". Immunity. 1 (3): 167–78. doi:10.1016/1074-7613(94)90095-7. PMID 7534202.
  4. ↑ Chatzigeorgiou A, Lyberi M, Chatzilymperis G, Nezos A, Kamper E (2009). "CD40/CD40L signaling and its implication in health and disease". BioFactors. 35 (6): 474–83. doi:10.1002/biof.62. PMID 19904719.
  5. ↑ Carlring J, Altaher HM, Clark S, Chen X, Latimer SL, Jenner T, Buckle AM, Heath AW (May 2011). "CD154-CD40 interactions in the control of murine B cell hematopoiesis". Journal of Leukocyte Biology. 89 (5): 697–706. doi:10.1189/jlb.0310179. PMC 3382295. PMID 21330346.
  6. ↑ McWhirter SM, Pullen SS, Holton JM, Crute JJ, Kehry MR, Alber T (July 1999). "Crystallographic analysis of CD40 recognition and signaling by human TRAF2". Proceedings of the National Academy of Sciences of the United States of America. 96 (15): 8408–13. doi:10.1073/pnas.96.15.8408. PMC 17529. PMID 10411888.
  7. ↑ 7.0 7.1 7.2 7.3 Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J (February 1999). "Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40". Proceedings of the National Academy of Sciences of the United States of America. 96 (4): 1234–9. doi:10.1073/pnas.96.4.1234. PMC 15446. PMID 9990007.
  8. ↑ Malinin NL, Boldin MP, Kovalenko AV, Wallach D (February 1997). "MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1". Nature. 385 (6616): 540–4. doi:10.1038/385540a0. PMID 9020361.
  9. ↑ Hu HM, O'Rourke K, Boguski MS, Dixit VM (December 1994). "A novel RING finger protein interacts with the cytoplasmic domain of CD40". The Journal of Biological Chemistry. 269 (48): 30069–72. PMID 7527023.
  10. ↑ Ni CZ, Welsh K, Leo E, Chiou CK, Wu H, Reed JC, Ely KR (September 2000). "Molecular basis for CD40 signaling mediated by TRAF3". Proceedings of the National Academy of Sciences of the United States of America. 97 (19): 10395–9. doi:10.1073/pnas.97.19.10395. PMC 27035. PMID 10984535.
  11. ↑ 11.0 11.1 Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC (December 1997). "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". The EMBO Journal. 16 (23): 6914–25. doi:10.1093/emboj/16.23.6914. PMC 1170295. PMID 9384571.
  12. ↑ Ishida TK, Tojo T, Aoki T, Kobayashi N, Ohishi T, Watanabe T, Yamamoto T, Inoue J (September 1996). "TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling". Proceedings of the National Academy of Sciences of the United States of America. 93 (18): 9437–42. doi:10.1073/pnas.93.18.9437. PMC 38446. PMID 8790348.
  13. ↑ Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten JG, Dewulf N, de Boer M, Vandenabeele P, Huylebroeck D, Remacle JE (June 2000). "TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation". The Journal of Biological Chemistry. 275 (24): 18586–93. doi:10.1074/jbc.M000531200. PMID 10764746.
  14. ↑ Vonderheide RH (April 2018). "The Immune Revolution: A Case for Priming, Not Checkpoint". Cancer Cell. 33 (4): 563–569. doi:10.1016/j.ccell.2018.03.008. PMC 5898647. PMID 29634944.

External links

Further reading

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