TCIRG1

V-type proton ATPase 116 kDa subunit a isoform 3 is an is_associated_with::enzyme that in humans is encoded by the TCIRG1 is_associated_with::gene.

Function
Through alternate splicing, this gene encodes two protein is_associated_with::isoforms with similarity to subunits of the vacuolar ATPase (is_associated_with::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, is_associated_with::zymogen activation, and receptor-mediated is_associated_with::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 (is_associated_with::N-terminus truncated, lacks amino acid residues 1-216 of the long isoform)

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

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

Function
is_associated_with::Antibody targeting of TIRC7 reveals significant prevention of is_associated_with::inflammation in variety of is_associated_with::animal models e.g. rejection of transplanted kidney and heart is_associated_with::allografts as well as progression of arthritis and EAE. These therapeutic effects were accompanied with significant decreases of Th1 specific is_associated_with::cytokines e.g. is_associated_with::IFN-gamma, is_associated_with::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 supports the inhibitory signals induced via TIRC7 pathway during immune activation. Further evidence for the inhibitory role of TIRC7 during the course of is_associated_with::immune response is that prevention of is_associated_with::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 is_associated_with::in vitro and is_associated_with::in vivo exhibiting. A significant induced is_associated_with::memory cell subset and reduction of CTLA4 expression observed in TIRC7 knock out mice.

Ligand
The recently identified cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of is_associated_with::HLA DR protein. Upon lymphocyte activation TIRC7 is upregulated to engage HLA-DRα2 and induce apoptotic signals in human is_associated_with::CD4+ and CD8+ T-cells. The down-regulation of the immune response is achieved via activation of the intrinsic apoptotic pathway by is_associated_with::caspase 9, inhibition of lymphocyte proliferation, is_associated_with::SHP-1 recruitment, decrease in is_associated_with::phosphorylation of is_associated_with::STAT4, TCR-ζ chain and is_associated_with::ZAP70 as well as inhibition of is_associated_with::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 is_associated_with::proinflammatory as well as inflammatory cytokines and induction of is_associated_with::apoptosis. These results strongly support the regulatory role of TIRC7 is_associated_with::signalling pathway in is_associated_with::lymphocytes.

Clinical significance
Mutations in this gene are associated with infantile malignant is_associated_with::osteopetrosis.