GP-1.2

Atp6v0a3 gene encodes for two alternative products, Tirc7 and a3 proteins, which are differentially expressed in activated T cells and resorbing osteoclasts, respectively. Tirc7 plays a central role in T cell activation, while a3 protein is critical for osteoclast‐mediated bone matrix resorption. Based on the large body of evidences documenting the relationships between T cells and osteoclasts, we hypothesized that the extracellular C‐terminus of Tirc7 protein could directly interact with osteoclast precursor cells. To address this issue, we performed the molecular cloning of a mouse Atp6v0a3 cDNA segment encoding the last 40 amino acids of Tirc7 protein, and we used this peptide as a ligand added to mouse osteoclast precursor cells. We evidenced that Tirc7‐Cter peptide induced the differentiation of RAW264.7 cells into osteoclast‐like cells, stimulated an autocrine/paracrine regulatory loop potentially involved in osteoclastic differentiation control, and strongly up‐regulated F4/80 protein expression within multinucleated osteoclast‐like cells. Using a mouse bone marrow‐derived CD11b+ cell line, or total bone marrow primary cells, we observed that similarly to Rankl, Tirc7‐Cter peptide induced the formation of TRACP‐positive large multinucleated cells. At last, using mouse primary monocytes purified from total bone marrow, we determined that Tirc7‐Cter peptide induced the appearance of small multinucleated cells (3–4 nuclei), devoid of resorbing activity, and which displayed modulations of dendritic cell marker genes expression. In conclusion, we report for the first time on biological effects mediated by a peptide corresponding to the C‐terminus of Tirc7 protein, which interfere with monocytic differentiation pathways. J. Cell. Physiol. 227: 3088–3098, 2012. © 2011 Wiley Periodicals, Inc.

The membrane protein T-cell immune response cDNA 7 (TIRC7) is transiently expressed in subsets of lymphocytes following antigen stimulation. The importance of TIRC7 in immune activation is demonstrated by the effect of antibodies directed against extracellular domains of TIRC7. In vitro targeting of TIRC7 inhibits proliferation and cytokine expression in human, mouse and rat lymphocytes, and these inhibitory effects have been associated with induction of cytotoxic T-lymphocyte antigen 4 mRNA and protein in the presence of TIRC7 antibodies. In vivo, anti-TIRC7 antibodies prevent kidney transplant rejection in rats and heart allograft rejection in mice. Treatment with an anti-TIRC7 antibody as monotherapy or in combination with TNFalpha blockade inhibits disease progression in collagen-induced arthritis. TIRC7 expression decreases in the peripheral blood of humans who have undergone cardiac transplant prior to clinical rejection, and is therefore a promising noninvasive tool for the prediction of rejection. Thus, targeting of TIRC7 may lead to the development of specific and effective therapeutic and diagnostic approaches by unifying relevant cellular and molecular responses in T- and B-cell subsets, and represents a promising new pathway for immune regulation in transplantation and autoimmune disease.