TCIRG1

• OMIM: 604 592
• UniProt: Q13488

The V- ATPase subunit A is a protein in the cell and Vakuolenmembranen many organisms. It is a subunit of V-ATPase complex, more specifically the sub-unit A of the V -ATPase proton channel. As such, it is essential for endocytosis and the normal function of lysosomes as a proton pump. The short isoform of the subunit ( TIRC7 ), however, acting on the activation of T - cells in the immune response. Mutations that affect the long isoform have the rare hereditary disease autosomal recessive osteopetrosis result ..

By alternative splicing of the gene encoding TCIRG1 two proteins with different functions. The long isoform (also OC116 ) acts as a V -ATPase subunit exclusively in osteoclasts. The short isoform, which lacks the first 216 amino acids, is usually referred to as TIRC7 (of English. T -cell immune response cDNA 7). It is expressed in lymphoid tissue, and on T-lymphocytes and is normal T-cell activation essential.

Short isoform ( TIRC7 )

Gene expression

TIRC7 is a membrane protein, which is induced after activation of the immune system on the surface of cells, and both on different peripheral human T- cells and B- cells as well as monocytes, and IL- 10 -expressing regulatory T cells. TIRC7 is colocalized during the immune response within the immunological synapse with the T -cell receptor and CTLA4. On the protein and mRNA level, the TIRC7 expression is upregulated in the following tissues and disease: lymphocytes of the synovial fluid of patients with rheumatoid arthritis, while the rejection of organ transplants, after bone marrow transplantation as well as in brain tissue of patients with multiple sclerosis.

Function

By treatment with the anti- TIRC7 antibody to the rejection of allogeneic kidney and Herztransplanate, on the other hand, the progression of rheumatoid arthritis and EAE be prevented in a variety of animal models, on the one hand an inflammation. These therapeutic effects of a unique reducing Th1 - specific cytokines such as interferon (IFN) -gamma, tumor necrosis factor (TNF) -alpha, interleukin-2 ( expression and transcription) as well as induction of CTLA4 accompanied, while the IL-10 expression is not affected. The induction of TIRC7 in IL-10 -secreting regulatory T cells and the avoidance of the presence of TIRC7 Colitisin -positive regulatory T cells supports the hypothesis of the induction of inhibitory signals through the TIRC7 pathway during immune activation. Further evidence of the inhibitory role of TIRC7 is that the occurrence of the disease was through the transfer of TIRC7 -positive cells in the CD45RO mouse model can be prevented before induction of colitis. The negative immunoregulatory role of TIRC7 is further supported by the fact that the TIRC7 knockout mouse has an increased T- and B -cell response in the presence of a variety of different stimuli in vitro and in vivo. In the TIRC7 knockout mouse also significantly induced memory T cell population, and a reduction of the expression of CTLA4 is observed.

Ligand

The recently identified Zelloberflächenligand of TIRC7 is the non- polymorphic alpha 2 domain (HLA- DRα2 ) of HLA-DR (see Human Leukocyte Antigen ). By T-cell activation TIRC7 is upregulated in order to bind HLA- DRα2 and apoptotic signals in human CD4 - and to induce CD8 T cells. The down-regulation of the immune response is achieved by the activation of the intrinschen pathway of apoptosis by the caspase 9, the inhibition of lymphocyte division, the binding of SHP-1, the reduction of the phosphorylation of STAT4, TCR ζ and ZAP70 and inhibition of FasL expression. HLA DRα2 TIRC7 and are co- localized at the point of contact of antigen-presenting cell and T- cell. In vivo, activation of HLA-DR TIRC7 pathway in lipopolysaccharide (LPS) activated lymphocytes by soluble HLA- DRα2 to inhibition of pro-inflammatory and inflammatory cytokines and the induction of apoptosis. These results strongly support the regulatory role of TIRC7 signal pathway in lymphocytes.