Attractin (DPPT-L), a member of the CUB family of cell adhesion and guidance proteins, is secreted by activated human T lymphocytes and modulates immune cell interactions

Abstract

Attractin is a normal human serum glycoprotein of 175 kDa that is rapidly expressed on activated T cells and released extracellularly after 48-72 hr. We have cloned attractin and find that, as in its natural serum form, it mediates the spreading of monocytes that become the focus for the clustering of nonproliferating T lymphocytes. There are two mRNA species with hematopoietic tissue-specific expression that code for a 134-kDa protein with a putative serine protease catalytic serine, four EGF-like motifs, a CUB domain, a C type lectin domain, and a domain homologous with the ligand-binding region of the common ␥ cytokine chain. Except for the latter two domains, the overall structure shares high homology with the Caenorhabditis elegans F33C8.1 protein, suggesting that attractin has evolved new domains and functions in parallel with the development of cell-mediated immunity.

Secreted and membrane attractin result from alternative splicing of the humanATRNgene

“…A predicted Caenorhabditis elegans protein, F33C8.1, is also homologous to attractin and is a transmembrane rather than a soluble protein (2). These results lead to the proposition that there exists a human membrane attractin in addition to the secreted form.…”

“…Germ-line mutations in the DNA-binding domain of Ikaros lead to animals devoid of T cells, B cells, and NK cells. There are three sites for NF-AT, nevertheless there is no evidence of an up-regulation of attractin mRNA after activation (2). Additional evidence that the role of NF-AT may be limited is that stimulation with phorbol 12-myristate 13-acetate͞ionomycin is known to up-regulate NF-AT activity, but such stimulation does not induce attractin expression.…”

“…We had noted previously a differential expression of the two attractin mRNA species (4.5 kb and 9 kb) in different lymphoid tissues (2). In particular, the 4.5-kb isoform was almost absent from thymus, although the higher 9-kb form was present at low levels, and the low 4.5-kb form appeared to be preferentially expressed in peripheral blood leukocytes (PBLs).…”

“…We recently have identified the soluble human plasma protein attractin as a molecule that can facilitate initial immune cell clustering (2) and, through a putative dipeptidyl peptidase IV (DPPIV) activity similar to that of CD26 (3), has the potential to regulate chemotactic activity of chemokines (4). These activities would be required at differing stages of the inflammatory process and suggest that the functional activities of attractin may operate independent of its actual plasma levels, much as is seen for the components of complement that circulate normally at constant levels but are only active in the context of ''fixed'' antibody during the effector phase of a humoral response.…”

Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26

“…Administration of chemical inhibitors of DPP IV activity leads to increased levels of GLP-1 in the circulation and causes enhanced insulin secretion and improved glucose tolerance in normal and diabetic animals (13)(14)(15)(16). However, the precise molecular target of these pharmacological inhibitors has not been identified, in part because of the multiplicity of enzymes exhibiting DPP IV-like activity (17)(18)(19)(20)(21). The aim of this study was to clarify the physiological role of CD26 and determine its contribution to blood glucose control.…”