TIRC7

PBB_Controls
update_page = no
require_manual_inspection = no
update_protein_box = yes
update_summary = yes
update_citations = yes

GNF_Protein_box


image_source =
PDB =
Name = T-cell immune response cDNA 7, T-cell immune regulator 1, transcript variant 2, isoform b (TIRC7)
HGNCid = 11647
Symbol = TIRC7
AltSymbols =
OMIM = 604592
GeneAtlas_

Orthologs = GNF_Ortholog_box
Hs_EntrezGene = 10312
Hs_Ensembl = ENSG00000110719
Hs_RefseqProtein = NP_006044
Hs_RefseqmRNA = NM_006053.2
Hs_GenLoc_db =
Hs_GenLoc_chr = 11
Hs_GenLoc_start = 67563059
Hs_GenLoc_end = 67574941

T-cell immune response cDNA 7, also known as TIRC7, is an alternate splice product of the human gene TCIRG1 located on chromosome 11. cite web | title = Entrez Gene: TCIRG1 T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10312| accessdate = ] [*cite journal | author=Heinemann T, Bulwin GC, Randall J, "et al." |title=Genomic organization of the gene coding for TIRC7, a novel membrane protein essential for T cell activation. |journal=Genomics |volume=57 |issue= 3 |pages= 398-406 |year= 1999 |pmid= 10329006 |doi= 10.1006/geno.1999.5751 ]

PBB_Summary
section_title =
summary_text = Through alternate splicing, this gene encodes two proteins (transcript 1, isoform a also named OC116 and transcript 2, isoform b also named TIRC7) with different functions. 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. The encoded isoform (b) is shorter than isoform a. cite web | title = NCBI Nucleotide: Homo sapiens T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3 (TCIRG1)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?db=nuccore&cmd=search&term=TIRC7| accessdate = ]

TIRC7

Expression

TIRC7 is a membrane protein induced after immune activation [*cite journal | author=Utku N, Heinemann T, Tullius SG, "et al." |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 |year= 1998 |pmid= 9806637 |doi= ] 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 [*cite journal | author= 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= J Immunol. |volume= 177|issue= 10 |pages= 6833-41|year= 2006|pmid= 17082597|doi= ] [ *cite journal | author= Valk E, Rudd CE, Schneider H.
title= CTLA-4 trafficking and surface expression.
journal= Trends Immunol. |volume= 29 |issue= 6 |pages= 272-9|year= 2008|pmid= 18468488|doi= ] At protein and mRNA level, its expression is induced in lymphocytes in synovial tissues obtained from patients with rheumatoid arthritis [ *cite journal | author= 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|year= 2006|pmid= 16542376|doi= ] [ *cite journal | author= 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|doi= ] or during rejection of solid organ transplants [ *cite journal | author= 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|year= 2005|pmid= 15883619|doi= ] [ *cite journal | author= 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= ] [ *cite journal | author= 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|year= 2001 |pmid= 11295466|doi= ] and bone marrow transplantation [ *cite journal | author= 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|year= 2007|pmid= 17378698|doi= ] as well as in brain tissues obtained from patients with multiple sclerosis. [ *cite journal | author= 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= ] [ *cite journal | author= Sellebjerg F, Datta P, Larsen J, Rieneck K, Alsing I, Oturai A, Svejgaard A, Soelberg Sørensen P, Ryder L.|title= Gene expression analysis of interferon-{beta} treatment in multiple sclerosis.|journal= Mult Scler. |volume= 14|issue= 5|pages= 615-21|year= 2008|pmid= 18408020|doi= ]

Function

Antibody targeting of TIRC7 reveals significant prevention of inflammation in variety of animal models e.g. rejection of transplanted kidney and heart allografts [ *cite journal | author= 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|year= 2006|pmid= 17138060|doi= ] [*cite journal | author= 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 |year= 2004|pmid= 15023142|doi= ] 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 [ *cite journal | author= 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= J Immunol. |volume= 180|issue= 9|pages= 6054-63|year= 2008|pmid= 18424726|doi= ] supports the inhibitory signals induced via TIRC7 pathway during immune activation [ *cite journal | author= Utku N, Heinemann T, Milford EL.|title = T-cell immune response cDNA 7 in allograft rejection and inflammation. |journal = Curr Opin Investig Drugs. |volume= 8|issue= 5|pages= 401-10|year= 2007|pmid= 17520869|doi= ] . A 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 [ *cite journal | author= 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= J Immunol. |volume=173 |issue= 4 |pages= 2342-52 |year= 2004 |pmid=15294947 |doi= ] .

Ligand

The recently identified cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of HLA DR protein [ *cite journal | author= 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|doi= ] . 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.

References

ee also

* T cell
* Co-stimulation
* MHC class II
* CTLA-4
* apoptosis