Plays a role as inhibitor of T-cells proliferation induced by CD3. Inhibits expression of IL2RA on activated T-cells and secretion of IL2. Inhibits tyrosine kinases that are required for IL2 production and cellular proliferation. Inhibits phospholipase C-gamma-1/PLCG1 phosphorylation and subsequent CD3-induced changes in intracellular free calcium. Prevents nuclear translocation of nuclear factor of activated T-cell to the nucleus. Plays a role in the inhibition of T-cell proliferation via IL10 secretion by cutaneous dendritic cells. May be a marker of CD4(+) CD56(+) leukemic tumor cells.
Ligation of the V7 (CD101) molecule on T cells with anti-V7 mAb blocks TCR/CD3-induced proliferation by inhibiting IL-2 transcription. To explore the basis for this observation, we analyzed the effects of V7 ligation on CD3/TCR-induced changes in intracellular free Ca2+ and Ca2+-dependent nuclear factor of activated T cells (NF-AT) translocation to the nucleus, which is required for IL-2 transcription. T cells exposed to anti-V7 mAb fluxed Ca2+ transiently, but did not flux Ca2+ in response to subsequent treatment with anti-CD3; however, they recovered the capacity to flux Ca2+ after treatment with pervanadate, indicating that tyrosine dephosphorylation of a critical V7-related substrate is required in the desensitization process. One such substrate, phospholipase C (PLC)-gamma1, becomes tyrosine phosphorylated on CD3/TCR activation and mediates inositol triphosphate-dependent Ca2+ flux. Co-cross-linking of T cells with anti-CD3 and anti-V7 resulted in selective inhibition of PLC-gamma1 tyrosine phosphorylation, which may explain V7-mediated blockade of anti-CD3-induced Ca2+ flux. Moreover, anti-CD3-induced binding of transcription factors to a consensus NF-AT-binding oligonucleotide, which is dependent on Ca2+, was blocked completely by treatment of the cells with anti-V7, whereas binding to a consensus-activating protein-1 oligonucleotide was unaffected. Western blot analysis of cytoplasmic and nuclear extracts confirmed that anti-V7 prevented nuclear translocation of NF-ATc induced by anti-CD3. We conclude that V7 ligation interferes with T cell activation and IL-2 secretion through a Ca2+ and tyrosine kinase-dependent pathway that inhibits PLC-gamma1 phosphorylation and prevents NF-AT translocation to the nucleus.
Previous studies have demonstrated that a mAb that recognizes the leukocyte surface Ag V7 inhibits TCR/CD3-dependent T cell activation. In the current study, we demonstrate that in addition to inhibiting T cell proliferation and IL-2 production, anti-V7 blocks tyrosine phosphorylation of TCR/CD3-associated substrates. PMA overcomes this effect, and both PMA and exogenous IL-2 overcome anti-V7-mediated inhibition of T cell proliferation and IL-2 production. T cells stimulated with anti-CD3 in the absence of CD28 or V7 ligation become unresponsive (anergic) to restimulation with anti-CD3; T cells primed in the presence of either anti-V7 or anti-CD28 retain their ability to respond to restimulation with anti-CD3. When T cells are primed in the presence of optimal concentrations of anti-V7 and anti-CD28 Abs, they proliferate normally, indicating that the costimulatory signals generated through CD28 dominate the inhibitory signals generated through V7. However, as the anti-CD28 stimulus is diluted, the V7 effect becomes dominant and proliferation is inhibited. Thus, although both anti-V7 and anti-CD28 Abs prevent anergy, they induce distinct, competing intracellular signals. Wortmannin, which blocks phosphoinositol 3-kinase-dependent signaling, has little effect on V7-mediated inhibition, while herbimycin, an inhibitor of tyrosine kinase, synergizes with anti-V7 to inhibit T cell activation. On the basis of these findings, V7-mediated signals appear to inhibit TCR-dependent tyrosine kinases that are required for IL-2 production and cellular proliferation.
Since the CD101 molecule is expressed on a major subpopulation of HLA-DR(+), CD1a(+), CD1c(+) cutaneous dendritic cells (DC), we studied the functional role of CD101 on cutaneous DC. Anti-CD101 monoclonal antibody (mAb) inhibited the proliferation of T cells induced by cutaneous DC. There was a synergistic inhibition between anti-CD101 mAb and anti-CD86/anti-CD80 mAb. Anti-CD101 mAb exerted its inhibitory effect when binding to the CD101 expressed on cutaneous DC. No positive role of CD101 putative ligand expressed by T cells in T cell proliferation was demonstrated, as T cells proliferated in response to soluble anti-CD3 mAb in the presence of CD86-transfected cells but not in the presence of CD101-transfected cells. Of major significance is the fact that IL-10 was produced by cutaneous DC after CD101 triggering with anti-CD101 mAb, while IL-10 secretion was up-regulated in mixed cutaneous DC-T cell cultures after CD101 triggering. Furthermore, IL-10-neutralizing mAb could reverse the inhibition induced by anti-CD101 mAb. Our results demonstrate that the CD101 triggering on cutaneous DC inhibits T cell proliferation via IL-10 production, suggesting an important regulatory role played by the CD101 molecule on DC during T cell activation.
Among a panel of mouse mAbs generated to a human T cell clone, one mAb, V7.1, inhibited T cell activation in the mixed lymphocyte reaction and was studied further. V7.1 reacted strongly with Ag-specific T cell clones, in addition to freshly isolated monocytes and granulocytes. However, the mAb reacted weakly with freshly isolated PBLs (T cells, B cells, and NK cells), T cells stimulated with phytohemagglutinin, or Con A, and did not stain the vast majority of transformed cell lines of hemopoietic origin. Stimulation of T cells with anti-CD3, or the combination of anti-CD3 and PMA, or anti-CD3, PMA and ionomycin, markedly increased V7.1 surface staining. The mAb precipitated a single polypeptide chain of approximately 135 kDa from alloactivated T cells or monocytes, which was reduced to approximately 110 kDa after treatment with N-glycanase. The proliferative response of T cells to allogeneic monocytes or B lymphoblastoid cells was inhibited by V7.1, and inhibition was maximal when the mAb was present at the initiation of culture. V7.1 also exhibited dose-dependent inhibition of the T cell response to immobilized anti-CD3 Ab in the absence of APCs, indicating that the inhibitory effect of this Ab occurs at the T cell level. Expression of CD25 (IL-2R) on anti-CD3-activated T cells and secretion of IL-2 induced with anti-CD3 and PMA were inhibited by V7.1, whereas the Ab had no effect on T cell proliferation induced by PHA or Con A or on T cell-mediated cytotoxicity. These results indicate that V7.1 recognizes a novel leukocyte surface glycoprotein, designated V7, that is up-regulated on Ag but not lectin-activated T cells, and appears to play a role in TCR/CD3-dependent T cell activation. In an accompanying study, the gene encoding the V7 Ag is described and the molecule is shown to be a novel member of the Ig superfamily.
CD101 was first described in our laboratory using two different monoclonal antibodies, BA27 and BB27, recognizing a 140-kDa disulfide-bonded homodimeric polypeptide on a small subset of circulating T lymphocytes and on most activated T cells in vitro. Further, it has been reported that most intestinal mucosal T lymphocytes expressed CD101. The gene coding for the CD101 antigen has been cloned and found to be identical to the gene coding for the recently described V7 antigen, corresponding to a type I trans-membrane protein with seven immunoglobulin-like loops in its extracellular domain. To define surface proteins that are involved in skin dendritic cell (DC) localization or function, we looked for the expression of CD1O1 on skin DC migrating from human skin explants. The majority of these DC had a phenotype of Langerhans cell (LC)-like mature DC, i.e., HLA-DR+ CD1a+ CD1c+ CD11a+ CD11c+ CD40+ CD50+ CD54+ CD58+ CD80+ CD83+ CD86+. We found that CD101 was expressed by a major subset of these HLA-DR+ CD1a+ CD1c+ LC-like skin DC. Next, we studied the effect of anti-CD101 monoclonal antibodies on primary allogeneic and on soluble antigen-specific mixed skin DC-lymphocyte reactions. We showed that two different monoclonal antibodies, BB27 and V7.1, inhibited the T-lymphocyte proliferative responses and that the inhibitory effect was overcome by high doses of exogenous IL-2. As both DC and T lymphocytes expressed CD101 molecules, we determined that the inhibitory effect was achieved both at the responder T-cell level and at the DC level. Thus, CD101 which is expressed on a subset of circulating T lymphocytes, has also been found on a subpopulation of LC-like DC. This molecule plays a major role in the activation of T cells by skin DC.
A series of molecular signals initiated by activation of a receptor on the surface of a cell. The pathway begins with binding of an extracellular ligand to a cell surface receptor, or for receptors that signal in the absence of a ligand, by ligand-withdrawal or the activity of a constitutively active receptor. The pathway ends with regulation of a downstream cellular process, e.g. transcription.
V7 is a cell surface glycoprotein expressed on Ag-activated T cells, monocytes, and granulocytes, as well as subpopulations of T cells and accessory cells present in thymic medulla and tonsil. A mAb directed against V7 inhibits the proliferative response of T cells to allogeneic cells or immobilized anti-CD3 Ab, but not lectin mitogens, suggesting that V7 plays a role in TCR/CD3-mediated T cell activation. We have used the anti-V7 Ab in eukaryotic expression cloning experiments to isolate a cDNA clone containing a 3,340-bp insert that encodes V7 when transiently expressed in simian and murine fibroblastoid cells. DNA sequence analysis revealed a novel 1,021-amino acid open reading frame the structure of which conforms to the category of type I integral membrane proteins. The protein sequence includes a 20-residue putative hydrophobic signal sequence followed by a putative extracellular domain of 934 amino acids, a prototypic hydrophobic transmembrane spanning a domain of 25 residues, and finally a short and highly charged putative cytoplasmic domain of 42 residues. The extracellular domain contains seven pairs of regularly spaced cysteine residues, suggestive of Ig-like domains. On the basis of statistical analysis of the sequences of the putative cysteine loops, all seven of the Ig-like domains belong to the variable, or V-type, category. By using fluorescence in situ hybridization, we have mapped the V7 gene to human chromosome Ip13. Thus, the V7 glycoprotein represents a novel member of the Ig superfamily that is involved in critical intracellular signals essential for immune function.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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