TCIRG1 explained

The TCIRG1 (T cell immune regulator 1) gene encodes for the V-type proton ATPase (V-ATPase) 116 kDa subunit a isoform 3 enzyme.

Gene

TCIRG1 (T cell immune regulator 1) is a gene that encodes the V-type proton ATPase (V-ATPase) 116 kDa subunit a isoform 3 enzyme.[1]

Function

Through alternate splicing, the TCIRG1 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:

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.

TIRC7

TIRC7 is a 75 kDa membrane protein, first described in 1998, that plays a central role in T cell activation.

Expression

TIRC7 is induced after immune activation 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.[2] [3] At the protein and mRNA level, its expression is induced in lymphocytes in synovial tissues obtained from patients with rheumatoid arthritis[4] [5] or during rejection of solid organ transplants[6] [7] [8] and bone marrow transplantation[9] as well as in brain tissues obtained from patients with multiple sclerosis.[10] [11]

Function

Antibody targeting of TIRC7 suppresses T cell activation and IL-2 secretion. Specifically, significant prevention of inflammation in a variety of animal models has been shown. These include rejection of transplanted kidney and heart allografts[12] [13] as well as progression of arthritis and experimental autoimmune encephalomyelitis (EAE). These 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[14] supports the inhibitory signals induced via TIRC7 pathway during immune activation.[15] 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.[16]

Ligand

The cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of HLA DR protein.[17] 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

TCIRG1 mutations affect the a3 subunit of the vacuolar proton pump, which in turn affects the acidification of the bone-osteoclast interface, resulting in infantile malignant osteopetrosis.[18] [19]

See also

Bibliography

Journal articles
Websites

Notes and References

  1. Li YP, Chen W, Stashenko P . Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit . Biochemical and Biophysical Research Communications . 218 . 3 . 813–21 . January 1996 . 8579597 . 10.1006/bbrc.1996.0145 .
  2. 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 . 6 . TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression . Journal of Immunology . 177 . 10 . 6833–41 . November 2006 . 17082597 . 10.4049/jimmunol.177.10.6833 . free .
  3. Valk E, Rudd CE, Schneider H . CTLA-4 trafficking and surface expression . Trends in Immunology . 29 . 6 . 272–9 . June 2008 . 18468488 . 4186961 . 10.1016/j.it.2008.02.011 .
  4. Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser P, Nieuwenhuis EE, Volk HD, Blumberg RS . 6 . Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice . Clinical and Experimental Immunology . 144 . 1 . 142–51 . April 2006 . 16542376 . 1809623 . 10.1111/j.1365-2249.2006.03044.x .
  5. Edwards CJ, Feldman JL, Beech J, Shields KM, Stover JA, Trepicchio WL, Larsen G, Foxwell BM, Brennan FM, Feldmann M, Pittman DD . 6 . Molecular profile of peripheral blood mononuclear cells from patients with rheumatoid arthritis . Molecular Medicine . 13 . 1–2 . 40–58 . 2007 . 17515956 . 1869619 . 10.2119/2006-000056.Edwards .
  6. Tamura A, Milford EL, Utku N . TIRC7 pathway as a target for preventing allograft rejection . Drug News & Perspectives . 18 . 2 . 103–8 . March 2005 . 15883619 . 10.1358/dnp.2005.18.2.877163 .
  7. Morgun A, Shulzhenko N, Diniz RV, Almeida DR, Carvalho AC, Gerbase-DeLima M . Cytokine and TIRC7 mRNA expression during acute rejection in cardiac allograft recipients . Transplantation Proceedings . 33 . 1–2 . 1610–1 . 2001 . 11267440 . 10.1016/S0041-1345(00)02613-0 .
  8. Shulzhenko N, Morgun A, Rampim GF, Franco M, Almeida DR, Diniz RV, Carvalho AC, Gerbase-DeLima M . 6 . Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans . Human Immunology . 62 . 4 . 342–7 . April 2001 . 11295466 . 10.1016/S0198-8859(01)00211-7 .
  9. 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 . 6 . Prediction of graft-versus-host disease in humans by donor gene-expression profiling . PLOS Medicine . 4 . 1 . e23 . January 2007 . 17378698 . 1796639 . 10.1371/journal.pmed.0040023 . free .
  10. Kopitzki K, Hart IK, Loehler J, Boerner A, Blumberg RS, DuPlessis D, Warneke P, Utku N . Improvement of acute and established EAE with TIRC7 mAb. J. Neuroimmunol. . 154. 88. 2004.
  11. Sellebjerg F, Datta P, Larsen J, Rieneck K, Alsing I, Oturai A, Svejgaard A, Soelberg Sørensen P, Ryder LP . 6 . Gene expression analysis of interferon-beta treatment in multiple sclerosis . Multiple Sclerosis . 14 . 5 . 615–21 . June 2008 . 18408020 . 10.1177/1352458507085976 . 206696484 .
  12. Kumamoto Y, Tamura A, Volk HD, Reinke P, Löhler J, Tullius SG, Utku N . TIRC7 is induced in rejected human kidneys and anti-TIRC7 mAb with FK506 prolongs survival of kidney allografts in rats . Transplant Immunology . 16 . 3–4 . 238–44 . November 2006 . 17138060 . 10.1016/j.trim.2006.09.027 .
  13. Kumamoto Y, Tomschegg A, Bennai-Sanfourche F, Boerner A, Kaser A, Schmidt-Knosalla I, Heinemann T, Schlawinsky M, Blumberg RS, Volk HD, Utku N . 6 . Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice . American Journal of Transplantation . 4 . 4 . 505–14 . April 2004 . 15023142 . 10.1111/j.1600-6143.2004.00367.x . 36001054 . free .
  14. Wakkach A, Augier S, Breittmayer JP, Blin-Wakkach C, Carle GF . 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 . May 2008 . 18424726 . 10.4049/jimmunol.180.9.6054 . free .
  15. Utku N, Heinemann T, Milford EL . T-cell immune response cDNA 7 in allograft rejection and inflammation . Current Opinion in Investigational Drugs . 8 . 5 . 401–10 . May 2007 . 17520869 .
  16. Utku N, Boerner A, Tomschegg A, Bennai-Sanfourche F, Bulwin GC, Heinemann T, Loehler J, Blumberg RS, Volk HD . 6 . 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 . August 2004 . 15294947 . 10.4049/jimmunol.173.4.2342 . free .
  17. 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 . 6 . 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 . February 2008 . 18270567 . 2217592 . 10.1371/journal.pone.0001576 . 2008PLoSO...3.1576B . Unutmaz . Derya . free .
  18. Penna S, Capo V, Palagano E, Sobacchi C, Villa A . One Disease, Many Genes: Implications for the Treatment of Osteopetroses . Frontiers in Endocrinology . 10 . 85 . 19 February 2019 . 30837952 . 10.3389/fendo.2019.00085 . 6389615 . free .
  19. Susani L, Pangrazio A, Sobacchi C, Taranta A, Mortier G, Savarirayan R, Villa A, Orchard P, Vezzoni P, Albertini A, Frattini A, Pagani F . 6 . TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA . Human Mutation . 24 . 3 . 225–35 . September 2004 . 15300850 . 10.1002/humu.20076 . 31788054 . free .

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