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{{Infobox_gene}}
{{Infobox_gene}}
'''V-type proton ATPase 116 kDa subunit a isoform 3''' is an [[enzyme]] that in humans is encoded by the ''TCIRG1'' [[gene]].<ref name="pmid8579597">{{cite journal | vauthors = Li YP, Chen W, Stashenko P | title = Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit | journal = Biochem Biophys Res Commun | volume = 218 | issue = 3 | pages = 813–21 |date=Mar 1996 | pmid = 8579597 | pmc = | doi = 10.1006/bbrc.1996.0145 }}</ref><ref name="pmid9806637">{{cite journal | vauthors = Utku N, Heinemann T, Tullius SG, Bulwin GC, Beinke S, Blumberg RS, Beato F, Randall J, Kojima R, Busconi L, Robertson ES, Schulein R, Volk HD, Milford EL, Gullans SR | title = Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein | journal = Immunity | volume = 9 | issue = 4 | pages = 509–18 |date=Nov 1998 | pmid = 9806637 | pmc = | doi =10.1016/S1074-7613(00)80634-2 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TCIRG1 T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10312| accessdate = }}</ref>
'''V-type proton ATPase 116 kDa subunit a isoform 3''' is an [[enzyme]] that in humans is encoded by the ''TCIRG1'' [[gene]].<ref name="pmid8579597">{{cite journal | vauthors = Li YP, Chen W, Stashenko P | title = Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit | journal = Biochem Biophys Res Commun | volume = 218 | issue = 3 | pages = 813–21 |date=Mar 1996 | pmid = 8579597 | doi = 10.1006/bbrc.1996.0145 }}</ref><ref name="pmid9806637">{{cite journal | vauthors = Utku N, Heinemann T, Tullius SG, Bulwin GC, Beinke S, Blumberg RS, Beato F, Randall J, Kojima R, Busconi L, Robertson ES, Schulein R, Volk HD, Milford EL, Gullans SR | title = Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein | journal = Immunity | volume = 9 | issue = 4 | pages = 509–18 |date=Nov 1998 | pmid = 9806637 | doi =10.1016/S1074-7613(00)80634-2 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TCIRG1 T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10312}}</ref>


== Function ==
== Function ==
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* short isoform b, also named '''TIRC7''' ([[N-terminus]] truncated, lacks amino acid residues 1-216 of the long isoform)
* short isoform b, also named '''TIRC7''' ([[N-terminus]] truncated, lacks amino acid residues 1-216 of the long isoform)


TIRC7 is expressed in [[T lymphocytes]] and is essential for normal [[T cell activation]]. This variant uses a [[Transcription (genetics)|transcription]] start site that is within [[exon]] 5 of variant 1 followed by an [[intron]] as part of its 5' UTR.<ref name="entrez2">{{cite web | title = NCBI Nucleotide: Homo sapiens T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3 (TCIRG1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=nuccore&cmd=search&term=TIRC7| accessdate = }}</ref>
TIRC7 is expressed in [[T lymphocytes]] and is essential for normal [[T cell activation]]. This variant uses a [[Transcription (genetics)|transcription]] start site that is within [[exon]] 5 of variant 1 followed by an [[intron]] as part of its 5' UTR.<ref name="entrez2">{{cite web | title = NCBI Nucleotide: Homo sapiens T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3 (TCIRG1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=nuccore&cmd=search&term=TIRC7}}</ref>


==TIRC7==
==TIRC7==
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===Expression ===
===Expression ===


TIRC7 is a [[Biological membrane|membrane]] [[protein]] induced after immune activation<ref name="pmid9806637" /> on the cell surface of certain peripheral human T and [[B cell]]s as well as [[monocyte]]s and [[Interleukin 10|IL-10]] expressing [[regulatory T cell]]s. During immune activation, TIRC7 is co-localized with the [[T cell receptor]] and [[CTLA4]] within the immune synapse of human [[T cell]]s<ref name="pmid17082597">{{cite journal | vauthors = Bulwin GC, Heinemann T, Bugge V, Winter M, Lohan A, Schlawinsky M, Schulze A, Wälter S, Sabat R, Schülein R, Wiesner B, Veh RW, Löhler J, Blumberg RS, Volk HD, Utku N | title = TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression | journal = Journal of Immunology | volume = 177 | issue = 10 | pages = 6833–41 |date=November 2006 | pmid = 17082597 | doi = 10.4049/jimmunol.177.10.6833| url = | doi-access = free }}</ref><ref name="pmid18468488">{{cite journal | vauthors = Valk E, Rudd CE, Schneider H | title = CTLA-4 trafficking and surface expression | journal = Trends Immunol. | volume = 29 | issue = 6 | pages = 272–9 |date=June 2008 | pmid = 18468488 | doi = 10.1016/j.it.2008.02.011 | url = | pmc = 4186961 }}</ref> At the protein and [[mRNA]] level, its [[Gene expression|expression]] is induced in [[lymphocytes]] in [[synovial membrane|synovial]] tissues obtained from patients with [[rheumatoid arthritis]]<ref name="pmid16542376">{{cite journal | vauthors = Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser P, Nieuwenhuis EE, Volk HD, Blumberg RS | title = Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice | journal = Clin. Exp. Immunol. | volume = 144 | issue = 1 | pages = 142–51 |date=April 2006 | pmid = 16542376 | pmc = 1809623 | doi = 10.1111/j.1365-2249.2006.03044.x | url = }}</ref><ref name="pmid17515956">{{cite journal | vauthors = Edwards CJ, Feldman JL, Beech J, Shields KM, Stover JA, Trepicchio WL, Larsen G, Foxwell BM, Brennan FM, Feldmann M, Pittman DD | title = Molecular Profile of Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis | journal = Mol. Med. | volume = 13 | issue = 1–2 | pages = 40–58 | year = 2007 | pmid = 17515956 | pmc = 1869619 | doi = 10.2119/2006-000056.Edwards | url = }}</ref> or during rejection of solid organ transplants<ref name="pmid15883619">{{cite journal | vauthors = Tamura A, Milford EL, Utku N | title = TIRC7 pathway as a target for preventing allograft rejection | journal = Drug News Perspect. | volume = 18 | issue = 2 | pages = 103–8 |date=March 2005 | pmid = 15883619 | doi = 10.1358/dnp.2005.18.2.877163 | url = }}</ref><ref name="pmid11267440">{{cite journal | vauthors = Morgun A, Shulzhenko N, Diniz RV, Almeida DR, Carvalho AC, Gerbase-DeLima M | title = Cytokine and TIRC7 mRNA expression during acute rejection in cardiac allograft recipients | journal = Transplant. Proc. | volume = 33 | issue = 1–2 | pages = 1610–1 | year = 2001 | pmid = 11267440 | doi = 10.1016/S0041-1345(00)02613-0| url = }}</ref><ref name="pmid11295466">{{cite journal | vauthors = Shulzhenko N, Morgun A, Rampim GF, Franco M, Almeida DR, Diniz RV, Carvalho AC, Gerbase-DeLima M | title = Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans | journal = Hum. Immunol. | volume = 62 | issue = 4 | pages = 342–7 |date=April 2001 | pmid = 11295466 | doi = 10.1016/S0198-8859(01)00211-7| url = }}</ref> and [[bone marrow]] [[Organ transplantation|transplantation]]<ref name="pmid17378698">{{cite journal | vauthors = Baron C, Somogyi R, Greller LD, Rineau V, Wilkinson P, Cho CR, Cameron MJ, Kelvin DJ, Chagnon P, Roy DC, Busque L, Sékaly RP, Perreault C | title = Prediction of Graft-Versus-Host Disease in Humans by Donor Gene-Expression Profiling | journal = PLOS Med. | volume = 4 | issue = 1 | pages = e23 |date=January 2007 | pmid = 17378698 | pmc = 1796639 | doi = 10.1371/journal.pmed.0040023 | url = }} {{open access}}</ref> as well as in [[brain]] tissues obtained from patients with [[multiple sclerosis]].<ref>{{cite journal | vauthors= Kopitzki K, Hart IK, Loehler J, Boerner A, Blumberg RS, DuPlessis D, Warneke P, Utku N |title= Improvement of acute and established EAE with TIRC7 mAb|journal= J. Neuroimmunol. |volume= 154|issue= |pages= 88|year= 2004|pmid= |doi= }}</ref><ref name="pmid18408020">{{cite journal | vauthors = Sellebjerg F, Datta P, Larsen J, Rieneck K, Alsing I, Oturai A, Svejgaard A, Soelberg Sørensen P, Ryder LP | title = Gene expression analysis of interferon-beta treatment in multiple sclerosis | journal = Mult. Scler. | volume = 14 | issue = 5 | pages = 615–21 |date=June 2008 | pmid = 18408020 | doi = 10.1177/1352458507085976 | s2cid = 206696484 | url = }}</ref>
TIRC7 is a [[Biological membrane|membrane]] [[protein]] induced after immune activation<ref name="pmid9806637" /> on the cell surface of certain peripheral human T and [[B cell]]s as well as [[monocyte]]s and [[Interleukin 10|IL-10]] expressing [[regulatory T cell]]s. During immune activation, TIRC7 is co-localized with the [[T cell receptor]] and [[CTLA4]] within the immune synapse of human [[T cell]]s<ref name="pmid17082597">{{cite journal | vauthors = Bulwin GC, Heinemann T, Bugge V, Winter M, Lohan A, Schlawinsky M, Schulze A, Wälter S, Sabat R, Schülein R, Wiesner B, Veh RW, Löhler J, Blumberg RS, Volk HD, Utku N | title = TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression | journal = Journal of Immunology | volume = 177 | issue = 10 | pages = 6833–41 |date=November 2006 | pmid = 17082597 | doi = 10.4049/jimmunol.177.10.6833| doi-access = free }}</ref><ref name="pmid18468488">{{cite journal | vauthors = Valk E, Rudd CE, Schneider H | title = CTLA-4 trafficking and surface expression | journal = Trends Immunol. | volume = 29 | issue = 6 | pages = 272–9 |date=June 2008 | pmid = 18468488 | doi = 10.1016/j.it.2008.02.011 | pmc = 4186961 }}</ref> At the protein and [[mRNA]] level, its [[Gene expression|expression]] is induced in [[lymphocytes]] in [[synovial membrane|synovial]] tissues obtained from patients with [[rheumatoid arthritis]]<ref name="pmid16542376">{{cite journal | vauthors = Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser P, Nieuwenhuis EE, Volk HD, Blumberg RS | title = Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice | journal = Clin. Exp. Immunol. | volume = 144 | issue = 1 | pages = 142–51 |date=April 2006 | pmid = 16542376 | pmc = 1809623 | doi = 10.1111/j.1365-2249.2006.03044.x }}</ref><ref name="pmid17515956">{{cite journal | vauthors = Edwards CJ, Feldman JL, Beech J, Shields KM, Stover JA, Trepicchio WL, Larsen G, Foxwell BM, Brennan FM, Feldmann M, Pittman DD | title = Molecular Profile of Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis | journal = Mol. Med. | volume = 13 | issue = 1–2 | pages = 40–58 | year = 2007 | pmid = 17515956 | pmc = 1869619 | doi = 10.2119/2006-000056.Edwards }}</ref> or during rejection of solid organ transplants<ref name="pmid15883619">{{cite journal | vauthors = Tamura A, Milford EL, Utku N | title = TIRC7 pathway as a target for preventing allograft rejection | journal = Drug News Perspect. | volume = 18 | issue = 2 | pages = 103–8 |date=March 2005 | pmid = 15883619 | doi = 10.1358/dnp.2005.18.2.877163 }}</ref><ref name="pmid11267440">{{cite journal | vauthors = Morgun A, Shulzhenko N, Diniz RV, Almeida DR, Carvalho AC, Gerbase-DeLima M | title = Cytokine and TIRC7 mRNA expression during acute rejection in cardiac allograft recipients | journal = Transplant. Proc. | volume = 33 | issue = 1–2 | pages = 1610–1 | year = 2001 | pmid = 11267440 | doi = 10.1016/S0041-1345(00)02613-0}}</ref><ref name="pmid11295466">{{cite journal | vauthors = Shulzhenko N, Morgun A, Rampim GF, Franco M, Almeida DR, Diniz RV, Carvalho AC, Gerbase-DeLima M | title = Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans | journal = Hum. Immunol. | volume = 62 | issue = 4 | pages = 342–7 |date=April 2001 | pmid = 11295466 | doi = 10.1016/S0198-8859(01)00211-7}}</ref> and [[bone marrow]] [[Organ transplantation|transplantation]]<ref name="pmid17378698">{{cite journal | vauthors = Baron C, Somogyi R, Greller LD, Rineau V, Wilkinson P, Cho CR, Cameron MJ, Kelvin DJ, Chagnon P, Roy DC, Busque L, Sékaly RP, Perreault C | title = Prediction of Graft-Versus-Host Disease in Humans by Donor Gene-Expression Profiling | journal = PLOS Med. | volume = 4 | issue = 1 | pages = e23 |date=January 2007 | pmid = 17378698 | pmc = 1796639 | doi = 10.1371/journal.pmed.0040023 }} {{open access}}</ref> as well as in [[brain]] tissues obtained from patients with [[multiple sclerosis]].<ref>{{cite journal | vauthors= Kopitzki K, Hart IK, Loehler J, Boerner A, Blumberg RS, DuPlessis D, Warneke P, Utku N |title= Improvement of acute and established EAE with TIRC7 mAb|journal= J. Neuroimmunol. |volume= 154|pages= 88|year= 2004}}</ref><ref name="pmid18408020">{{cite journal | vauthors = Sellebjerg F, Datta P, Larsen J, Rieneck K, Alsing I, Oturai A, Svejgaard A, Soelberg Sørensen P, Ryder LP | title = Gene expression analysis of interferon-beta treatment in multiple sclerosis | journal = Mult. Scler. | volume = 14 | issue = 5 | pages = 615–21 |date=June 2008 | pmid = 18408020 | doi = 10.1177/1352458507085976 | s2cid = 206696484 }}</ref>


===Function===
===Function===


[[Antibody]] targeting of TIRC7 reveals significant prevention of [[inflammation]] in variety of [[animal model]]s e.g. [[Transplant rejection|rejection]] of transplanted kidney and heart [[allograft]]s<ref name="pmid17138060">{{cite journal | vauthors = Kumamoto Y, Tamura A, Volk HD, Reinke P, Löhler J, Tullius SG, Utku N | title = TIRC7 is induced in rejected human kidneys and anti-TIRC7 mAb with FK506 prolongs survival of kidney allografts in rats | journal = Transpl. Immunol. | volume = 16 | issue = 3–4 | pages = 238–44 |date=November 2006 | pmid = 17138060 | doi = 10.1016/j.trim.2006.09.027 | url = }}</ref><ref name="pmid15023142">{{cite journal | vauthors = Kumamoto Y, Tomschegg A, Bennai-Sanfourche F, Boerner A, Kaser A, Schmidt-Knosalla I, Heinemann T, Schlawinsky M, Blumberg RS, Volk HD, Utku N | title = Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice | journal = Am. J. Transplant. | volume = 4 | issue = 4 | pages = 505–14 |date=April 2004 | pmid = 15023142 | doi = 10.1111/j.1600-6143.2004.00367.x | s2cid = 36001054 | url = }}</ref> as well as progression of arthritis and EAE. These therapeutic effects were accompanied with significant decreases of [[Th1 cell|Th1]] specific [[cytokine]]s e.g. [[IFN-gamma]], [[TNF-alpha]], [[Interleukin 2|IL-2]] expression and transcription, induction of CTLA4 whereas IL-10 remained unchanged. The induction of TIRC7 in IL-10 secreting T regulatory cells and the prevention of colitis in the presence of TIRC7 positive T regulatory cells<ref name="pmid18424726">{{cite journal | vauthors = Wakkach A, Augier S, Breittmayer JP, Blin-Wakkach C, Carle GF | title = Characterization of IL-10-secreting T cells derived from regulatory CD4+CD25+ cells by the TIRC7 surface marker | journal = Journal of Immunology | volume = 180 | issue = 9 | pages = 6054–63 |date=May 2008 | pmid = 18424726 | doi = 10.4049/jimmunol.180.9.6054| url = | doi-access = free }}</ref> supports the inhibitory signals induced via TIRC7 pathway during immune activation.<ref name="pmid17520869">{{cite journal | vauthors = Utku N, Heinemann T, Milford EL | title = T-cell immune response cDNA 7 in allograft rejection and inflammation | journal = Current Opinion in Investigational Drugs | volume = 8 | issue = 5 | pages = 401–10 |date=May 2007 | pmid = 17520869 | doi = | url = }}</ref> Further evidence for the inhibitory role of TIRC7 during the course of [[immune response]] is that prevention of [[colitis]] was achievable by a transfer of TIRC7 positive [[Cell (biology)|cells]] into CD45RO mice prior to induction of colitis. The negative immune regulatory role of TIRC7 is furthermore supported by the fact that TIRC7 [[Gene knockout|knock out]] mice exhibits an increased T and B cell response in the presence of various stimuli [[in vitro]] and [[in vivo]] exhibiting. A significant induced [[Memory B cell|memory cell]] subset and reduction of CTLA4 expression observed in TIRC7 knock out mice.<ref name="pmid15294947">{{cite journal | vauthors = Utku N, Boerner A, Tomschegg A, Bennai-Sanfourche F, Bulwin GC, Heinemann T, Loehler J, Blumberg RS, Volk HD | title = TIRC7 deficiency causes in vitro and in vivo augmentation of T and B cell activation and cytokine response | journal = Journal of Immunology | volume = 173 | issue = 4 | pages = 2342–52 |date=August 2004 | pmid = 15294947 | doi = 10.4049/jimmunol.173.4.2342| url = | doi-access = free }}</ref>
[[Antibody]] targeting of TIRC7 reveals significant prevention of [[inflammation]] in variety of [[animal model]]s e.g. [[Transplant rejection|rejection]] of transplanted kidney and heart [[allograft]]s<ref name="pmid17138060">{{cite journal | vauthors = Kumamoto Y, Tamura A, Volk HD, Reinke P, Löhler J, Tullius SG, Utku N | title = TIRC7 is induced in rejected human kidneys and anti-TIRC7 mAb with FK506 prolongs survival of kidney allografts in rats | journal = Transpl. Immunol. | volume = 16 | issue = 3–4 | pages = 238–44 |date=November 2006 | pmid = 17138060 | doi = 10.1016/j.trim.2006.09.027 }}</ref><ref name="pmid15023142">{{cite journal | vauthors = Kumamoto Y, Tomschegg A, Bennai-Sanfourche F, Boerner A, Kaser A, Schmidt-Knosalla I, Heinemann T, Schlawinsky M, Blumberg RS, Volk HD, Utku N | title = Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice | journal = Am. J. Transplant. | volume = 4 | issue = 4 | pages = 505–14 |date=April 2004 | pmid = 15023142 | doi = 10.1111/j.1600-6143.2004.00367.x | s2cid = 36001054 }}</ref> as well as progression of arthritis and EAE. These therapeutic effects were accompanied with significant decreases of [[Th1 cell|Th1]] specific [[cytokine]]s e.g. [[IFN-gamma]], [[TNF-alpha]], [[Interleukin 2|IL-2]] expression and transcription, induction of CTLA4 whereas IL-10 remained unchanged. The induction of TIRC7 in IL-10 secreting T regulatory cells and the prevention of colitis in the presence of TIRC7 positive T regulatory cells<ref name="pmid18424726">{{cite journal | vauthors = Wakkach A, Augier S, Breittmayer JP, Blin-Wakkach C, Carle GF | title = Characterization of IL-10-secreting T cells derived from regulatory CD4+CD25+ cells by the TIRC7 surface marker | journal = Journal of Immunology | volume = 180 | issue = 9 | pages = 6054–63 |date=May 2008 | pmid = 18424726 | doi = 10.4049/jimmunol.180.9.6054| doi-access = free }}</ref> supports the inhibitory signals induced via TIRC7 pathway during immune activation.<ref name="pmid17520869">{{cite journal | vauthors = Utku N, Heinemann T, Milford EL | title = T-cell immune response cDNA 7 in allograft rejection and inflammation | journal = Current Opinion in Investigational Drugs | volume = 8 | issue = 5 | pages = 401–10 |date=May 2007 | pmid = 17520869 }}</ref> Further evidence for the inhibitory role of TIRC7 during the course of [[immune response]] is that prevention of [[colitis]] was achievable by a transfer of TIRC7 positive [[Cell (biology)|cells]] into CD45RO mice prior to induction of colitis. The negative immune regulatory role of TIRC7 is furthermore supported by the fact that TIRC7 [[Gene knockout|knock out]] mice exhibits an increased T and B cell response in the presence of various stimuli [[in vitro]] and [[in vivo]] exhibiting. A significant induced [[Memory B cell|memory cell]] subset and reduction of CTLA4 expression observed in TIRC7 knock out mice.<ref name="pmid15294947">{{cite journal | vauthors = Utku N, Boerner A, Tomschegg A, Bennai-Sanfourche F, Bulwin GC, Heinemann T, Loehler J, Blumberg RS, Volk HD | title = TIRC7 deficiency causes in vitro and in vivo augmentation of T and B cell activation and cytokine response | journal = Journal of Immunology | volume = 173 | issue = 4 | pages = 2342–52 |date=August 2004 | pmid = 15294947 | doi = 10.4049/jimmunol.173.4.2342| doi-access = free }}</ref>


=== Ligand ===
=== Ligand ===


The recently identified cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of [[HLA DR]] protein.<ref name="pmid18270567">{{cite journal | vauthors = Bulwin GC, Wälter S, Schlawinsky M, Heinemann T, Schulze A, Höhne W, Krause G, Kalka-Moll W, Fraser P, Volk HD, Löhler J, Milford EL, Utku N | title = HLA-DR Alpha 2 Mediates Negative Signalling via Binding to Tirc7 Leading to Anti-Inflammatory and Apoptotic Effects in Lymphocytes In Vitro and In Vivo | journal = PLOS ONE | volume = 3 | issue = 2 | pages = e1576 | year = 2008 | pmid = 18270567 | pmc = 2217592 | doi = 10.1371/journal.pone.0001576 | url = | editor1-last = Unutmaz | editor1-first = Derya }} {{open access}}</ref> Upon lymphocyte activation TIRC7 is upregulated to engage HLA-DRα2 and induce apoptotic signals in human [[CD4+]] and CD8+ T-cells. The down-regulation of the immune response is achieved via activation of the intrinsic apoptotic pathway by [[caspase]] 9, inhibition of lymphocyte proliferation, [[SHP-1]] recruitment, decrease in [[phosphorylation]] of [[STAT4]], TCR-ζ chain and [[ZAP70]] as well as inhibition of [[FasL]] expression. HLA-DRα2 and TIRC7 co-localize at the APC-T cell interaction site. ''In vivo'', triggering the HLA-DR-TIRC7 pathway in lipopolysaccaride ([[Lipopolysaccharide|LPS]]) activated lymphocytes using soluble HLA-DRα2 leads to inhibition of [[proinflammatory]] as well as [[inflammation|inflammatory]] cytokines and induction of [[apoptosis]]. These results strongly support the regulatory role of TIRC7 [[signalling pathway]] in [[lymphocyte]]s.
The recently identified cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of [[HLA DR]] protein.<ref name="pmid18270567">{{cite journal | vauthors = Bulwin GC, Wälter S, Schlawinsky M, Heinemann T, Schulze A, Höhne W, Krause G, Kalka-Moll W, Fraser P, Volk HD, Löhler J, Milford EL, Utku N | title = HLA-DR Alpha 2 Mediates Negative Signalling via Binding to Tirc7 Leading to Anti-Inflammatory and Apoptotic Effects in Lymphocytes In Vitro and In Vivo | journal = PLOS ONE | volume = 3 | issue = 2 | pages = e1576 | year = 2008 | pmid = 18270567 | pmc = 2217592 | doi = 10.1371/journal.pone.0001576 | editor1-last = Unutmaz | editor1-first = Derya }} {{open access}}</ref> Upon lymphocyte activation TIRC7 is upregulated to engage HLA-DRα2 and induce apoptotic signals in human [[CD4+]] and CD8+ T-cells. The down-regulation of the immune response is achieved via activation of the intrinsic apoptotic pathway by [[caspase]] 9, inhibition of lymphocyte proliferation, [[SHP-1]] recruitment, decrease in [[phosphorylation]] of [[STAT4]], TCR-ζ chain and [[ZAP70]] as well as inhibition of [[FasL]] expression. HLA-DRα2 and TIRC7 co-localize at the APC-T cell interaction site. ''In vivo'', triggering the HLA-DR-TIRC7 pathway in lipopolysaccaride ([[Lipopolysaccharide|LPS]]) activated lymphocytes using soluble HLA-DRα2 leads to inhibition of [[proinflammatory]] as well as [[inflammation|inflammatory]] cytokines and induction of [[apoptosis]]. These results strongly support the regulatory role of TIRC7 [[signalling pathway]] in [[lymphocyte]]s.


== Clinical significance ==
== Clinical significance ==
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{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal | vauthors=Finbow ME, Harrison MA |title=The vacuolar H+-ATPase: a universal proton pump of eukaryotes |journal=Biochem. J. |volume=324 |issue= Pt 3|pages= 697–712 |year= 1997 |pmid= 9210392 |doi= 10.1042/bj3240697| pmc=1218484 }}
*{{cite journal | vauthors=Finbow ME, Harrison MA |title=The vacuolar H+-ATPase: a universal proton pump of eukaryotes |journal=Biochem. J. |volume=324 |issue= Pt 3|pages= 697–712 |year= 1997 |pmid= 9210392 |doi= 10.1042/bj3240697| pmc=1218484 }}
*{{cite journal | vauthors=Stevens TH, Forgac M |title=Structure, function and regulation of the vacuolar (H+)-ATPase |journal=Annu. Rev. Cell Dev. Biol. |volume=13 |issue= |pages= 779–808 |year= 1998 |pmid= 9442887 |doi= 10.1146/annurev.cellbio.13.1.779 }}
*{{cite journal | vauthors=Stevens TH, Forgac M |title=Structure, function and regulation of the vacuolar (H+)-ATPase |journal=Annu. Rev. Cell Dev. Biol. |volume=13 |pages= 779–808 |year= 1998 |pmid= 9442887 |doi= 10.1146/annurev.cellbio.13.1.779 }}
*{{cite journal | vauthors=Nelson N, Harvey WR |title=Vacuolar and plasma membrane proton-adenosinetriphosphatases |journal=Physiol. Rev. |volume=79 |issue= 2 |pages= 361–85 |year= 1999 |pmid= 10221984 |doi= 10.1152/physrev.1999.79.2.361}}
*{{cite journal | vauthors=Nelson N, Harvey WR |title=Vacuolar and plasma membrane proton-adenosinetriphosphatases |journal=Physiol. Rev. |volume=79 |issue= 2 |pages= 361–85 |year= 1999 |pmid= 10221984 |doi= 10.1152/physrev.1999.79.2.361}}
*{{cite journal | author=Forgac M |title=Structure and properties of the vacuolar (H+)-ATPases |journal=J. Biol. Chem. |volume=274 |issue= 19 |pages= 12951–4 |year= 1999 |pmid= 10224039 |doi=10.1074/jbc.274.19.12951 |doi-access=free }}
*{{cite journal | author=Forgac M |title=Structure and properties of the vacuolar (H+)-ATPases |journal=J. Biol. Chem. |volume=274 |issue= 19 |pages= 12951–4 |year= 1999 |pmid= 10224039 |doi=10.1074/jbc.274.19.12951 |doi-access=free }}

Revision as of 14:07, 10 December 2020

TCIRG1
Identifiers
AliasesTCIRG1, ATP6N1C, ATP6V0A3, Atp6i, OC-116kDa, OC116, OPTB1, Stv1, TIRC7, Vph1, a3, T-cell immune regulator 1, ATPase H+ transporting V0 subunit a3, T cell immune regulator 1, ATPase H+ transporting V0 subunit a3
External IDsOMIM: 604592; MGI: 1350931; HomoloGene: 4392; GeneCards: TCIRG1; OMA:TCIRG1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10312

27060

Ensembl

ENSG00000110719

ENSMUSG00000001750

UniProt

Q13488

n/a

RefSeq (mRNA)

NM_006019
NM_006053
NM_001351059

NM_001136091
NM_001167784
NM_016921

RefSeq (protein)

NP_006010
NP_006044
NP_001337988

n/a

Location (UCSC)Chr 11: 68.04 – 68.05 MbChr 19: 3.95 – 3.96 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

V-type proton ATPase 116 kDa subunit a isoform 3 is an enzyme that in humans is encoded by the TCIRG1 gene.[5][6][7]

Function

Through alternate splicing, this gene encodes two protein isoforms with similarity to subunits of the vacuolar ATPase (V-ATPase) but the encoded proteins seem to have different functions. V-ATPase is a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain.

The two isoforms are:

  • long isoform a, also named OC116
  • short isoform b, also named TIRC7 (N-terminus truncated, lacks amino acid residues 1-216 of the long isoform)

TIRC7 is expressed in T lymphocytes and is essential for normal T cell activation. This variant uses a transcription start site that is within exon 5 of variant 1 followed by an intron as part of its 5' UTR.[8]

TIRC7

Expression

TIRC7 is a membrane protein induced after immune activation[6] on the cell surface of certain peripheral human T and B cells as well as monocytes and IL-10 expressing regulatory T cells. During immune activation, TIRC7 is co-localized with the T cell receptor and CTLA4 within the immune synapse of human T cells[9][10] At the protein and mRNA level, its expression is induced in lymphocytes in synovial tissues obtained from patients with rheumatoid arthritis[11][12] or during rejection of solid organ transplants[13][14][15] and bone marrow transplantation[16] as well as in brain tissues obtained from patients with multiple sclerosis.[17][18]

Function

Antibody targeting of TIRC7 reveals significant prevention of inflammation in variety of animal models e.g. rejection of transplanted kidney and heart allografts[19][20] as well as progression of arthritis and EAE. These therapeutic effects were accompanied with significant decreases of Th1 specific cytokines e.g. IFN-gamma, TNF-alpha, IL-2 expression and transcription, induction of CTLA4 whereas IL-10 remained unchanged. The induction of TIRC7 in IL-10 secreting T regulatory cells and the prevention of colitis in the presence of TIRC7 positive T regulatory cells[21] supports the inhibitory signals induced via TIRC7 pathway during immune activation.[22] Further evidence for the inhibitory role of TIRC7 during the course of immune response is that prevention of colitis was achievable by a transfer of TIRC7 positive cells into CD45RO mice prior to induction of colitis. The negative immune regulatory role of TIRC7 is furthermore supported by the fact that TIRC7 knock out mice exhibits an increased T and B cell response in the presence of various stimuli in vitro and in vivo exhibiting. A significant induced memory cell subset and reduction of CTLA4 expression observed in TIRC7 knock out mice.[23]

Ligand

The recently identified cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of HLA DR protein.[24] Upon lymphocyte activation TIRC7 is upregulated to engage HLA-DRα2 and induce apoptotic signals in human CD4+ and CD8+ T-cells. The down-regulation of the immune response is achieved via activation of the intrinsic apoptotic pathway by caspase 9, inhibition of lymphocyte proliferation, SHP-1 recruitment, decrease in phosphorylation of STAT4, TCR-ζ chain and ZAP70 as well as inhibition of FasL expression. HLA-DRα2 and TIRC7 co-localize at the APC-T cell interaction site. In vivo, triggering the HLA-DR-TIRC7 pathway in lipopolysaccaride (LPS) activated lymphocytes using soluble HLA-DRα2 leads to inhibition of proinflammatory as well as inflammatory cytokines and induction of apoptosis. These results strongly support the regulatory role of TIRC7 signalling pathway in lymphocytes.

Clinical significance

Mutations in this gene are associated with infantile malignant osteopetrosis.[7]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000110719 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001750 – 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. ^ Li YP, Chen W, Stashenko P (Mar 1996). "Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit". Biochem Biophys Res Commun. 218 (3): 813–21. doi:10.1006/bbrc.1996.0145. PMID 8579597.
  6. ^ a b Utku N, Heinemann T, Tullius SG, Bulwin GC, Beinke S, Blumberg RS, Beato F, Randall J, Kojima R, Busconi L, Robertson ES, Schulein R, Volk HD, Milford EL, Gullans SR (Nov 1998). "Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein". Immunity. 9 (4): 509–18. doi:10.1016/S1074-7613(00)80634-2. PMID 9806637.
  7. ^ a b "Entrez Gene: TCIRG1 T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3".
  8. ^ "NCBI Nucleotide: Homo sapiens T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3 (TCIRG1)".
  9. ^ Bulwin GC, Heinemann T, Bugge V, Winter M, Lohan A, Schlawinsky M, Schulze A, Wälter S, Sabat R, Schülein R, Wiesner B, Veh RW, Löhler J, Blumberg RS, Volk HD, Utku N (November 2006). "TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression". Journal of Immunology. 177 (10): 6833–41. doi:10.4049/jimmunol.177.10.6833. PMID 17082597.
  10. ^ Valk E, Rudd CE, Schneider H (June 2008). "CTLA-4 trafficking and surface expression". Trends Immunol. 29 (6): 272–9. doi:10.1016/j.it.2008.02.011. PMC 4186961. PMID 18468488.
  11. ^ Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser P, Nieuwenhuis EE, Volk HD, Blumberg RS (April 2006). "Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice". Clin. Exp. Immunol. 144 (1): 142–51. doi:10.1111/j.1365-2249.2006.03044.x. PMC 1809623. PMID 16542376.
  12. ^ Edwards CJ, Feldman JL, Beech J, Shields KM, Stover JA, Trepicchio WL, Larsen G, Foxwell BM, Brennan FM, Feldmann M, Pittman DD (2007). "Molecular Profile of Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis". Mol. Med. 13 (1–2): 40–58. doi:10.2119/2006-000056.Edwards. PMC 1869619. PMID 17515956.
  13. ^ Tamura A, Milford EL, Utku N (March 2005). "TIRC7 pathway as a target for preventing allograft rejection". Drug News Perspect. 18 (2): 103–8. doi:10.1358/dnp.2005.18.2.877163. PMID 15883619.
  14. ^ Morgun A, Shulzhenko N, Diniz RV, Almeida DR, Carvalho AC, Gerbase-DeLima M (2001). "Cytokine and TIRC7 mRNA expression during acute rejection in cardiac allograft recipients". Transplant. Proc. 33 (1–2): 1610–1. doi:10.1016/S0041-1345(00)02613-0. PMID 11267440.
  15. ^ Shulzhenko N, Morgun A, Rampim GF, Franco M, Almeida DR, Diniz RV, Carvalho AC, Gerbase-DeLima M (April 2001). "Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans". Hum. Immunol. 62 (4): 342–7. doi:10.1016/S0198-8859(01)00211-7. PMID 11295466.
  16. ^ Baron C, Somogyi R, Greller LD, Rineau V, Wilkinson P, Cho CR, Cameron MJ, Kelvin DJ, Chagnon P, Roy DC, Busque L, Sékaly RP, Perreault C (January 2007). "Prediction of Graft-Versus-Host Disease in Humans by Donor Gene-Expression Profiling". PLOS Med. 4 (1): e23. doi:10.1371/journal.pmed.0040023. PMC 1796639. PMID 17378698.{{cite journal}}: CS1 maint: unflagged free DOI (link) Open access icon
  17. ^ Kopitzki K, Hart IK, Loehler J, Boerner A, Blumberg RS, DuPlessis D, Warneke P, Utku N (2004). "Improvement of acute and established EAE with TIRC7 mAb". J. Neuroimmunol. 154: 88.
  18. ^ Sellebjerg F, Datta P, Larsen J, Rieneck K, Alsing I, Oturai A, Svejgaard A, Soelberg Sørensen P, Ryder LP (June 2008). "Gene expression analysis of interferon-beta treatment in multiple sclerosis". Mult. Scler. 14 (5): 615–21. doi:10.1177/1352458507085976. PMID 18408020. S2CID 206696484.
  19. ^ Kumamoto Y, Tamura A, Volk HD, Reinke P, Löhler J, Tullius SG, Utku N (November 2006). "TIRC7 is induced in rejected human kidneys and anti-TIRC7 mAb with FK506 prolongs survival of kidney allografts in rats". Transpl. Immunol. 16 (3–4): 238–44. doi:10.1016/j.trim.2006.09.027. PMID 17138060.
  20. ^ Kumamoto Y, Tomschegg A, Bennai-Sanfourche F, Boerner A, Kaser A, Schmidt-Knosalla I, Heinemann T, Schlawinsky M, Blumberg RS, Volk HD, Utku N (April 2004). "Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice". Am. J. Transplant. 4 (4): 505–14. doi:10.1111/j.1600-6143.2004.00367.x. PMID 15023142. S2CID 36001054.
  21. ^ Wakkach A, Augier S, Breittmayer JP, Blin-Wakkach C, Carle GF (May 2008). "Characterization of IL-10-secreting T cells derived from regulatory CD4+CD25+ cells by the TIRC7 surface marker". Journal of Immunology. 180 (9): 6054–63. doi:10.4049/jimmunol.180.9.6054. PMID 18424726.
  22. ^ Utku N, Heinemann T, Milford EL (May 2007). "T-cell immune response cDNA 7 in allograft rejection and inflammation". Current Opinion in Investigational Drugs. 8 (5): 401–10. PMID 17520869.
  23. ^ Utku N, Boerner A, Tomschegg A, Bennai-Sanfourche F, Bulwin GC, Heinemann T, Loehler J, Blumberg RS, Volk HD (August 2004). "TIRC7 deficiency causes in vitro and in vivo augmentation of T and B cell activation and cytokine response". Journal of Immunology. 173 (4): 2342–52. doi:10.4049/jimmunol.173.4.2342. PMID 15294947.
  24. ^ Bulwin GC, Wälter S, Schlawinsky M, Heinemann T, Schulze A, Höhne W, Krause G, Kalka-Moll W, Fraser P, Volk HD, Löhler J, Milford EL, Utku N (2008). Unutmaz D (ed.). "HLA-DR Alpha 2 Mediates Negative Signalling via Binding to Tirc7 Leading to Anti-Inflammatory and Apoptotic Effects in Lymphocytes In Vitro and In Vivo". PLOS ONE. 3 (2): e1576. doi:10.1371/journal.pone.0001576. PMC 2217592. PMID 18270567.{{cite journal}}: CS1 maint: unflagged free DOI (link) Open access icon

Further reading

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