Michael Schlesinger, The Hubert H Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

The Thy-1 antigen was discovered by Reif and Allen in 1964 as a mouse alloantigen distinguishing between the AKR/J mouse strain and many other inbred strains of mice. The antigen was initially called the © (theta) antigen, and its alloantigenic variants were called 0-AKR and ©-C3H, respectively. It was shown to be expressed preferentially in the nervous tissue of the mouse and on some lymphocytes, with a particular high level on thymocytes. When it became apparent that the AKR/Cum inbred strain possessed the 0-C3H rather than the ©-AKR alloantigen, and that rats possessed the ©-AKR determinant, the name of the (H) antigen was changed into Thy-1 and its alloantigenic variants became Thy-1.1 and Thy-1.2.

In 1969 the Thy-1 antigen was shown to be present on a distinct subset of mouse lymphocytes that became known as T lymphocytes. Schlesinger and Yron showed that the Thy-1 antigen was characteristic for those lymphocytes that disappeared from the peripheral lymphoid system upon neonatal thymectomy or following treatment with xenogeneic antilymphocyte scrum, while Raff showed that the antigen was virtually absent from the lymphoid system of nude mice.

The Thy-1 antigen was subsequently demonstrated in many other species, including humans, rats, dogs, chickens, frogs and even squids and tunicates. The tissue distribution of the Thy-1 antigen in the various species is, however, somewhat different. In almost all species studied, the Thy-1 antigen is present in the nervous tissue. In mice and rats Thy-1 was shown to be absent from glial cells but was found on neurons, with the exception of the primary olfactory neurons.

On the whole, the Thy-1 antigen has proven to be a very useful reagent for the detection and selection of the T lymphocyte subpopulation among the white blood cells of mice. Thy-1 could, however, also be detected at low concentrations on pluripotent hematopoietic stem cells in mice and in rats. The antigen was expressed on progenitor cells of the erythroid, myeloid and B lymphocyte pathway, but was absent from more mature stages of development. In humans, the Thy-1 differentiation antigen (CD90) is expressed on CD34+ hematopoietic progenitor cells isolated either from the bone marrow or from the peripheral blood.

Biochemical analysis of Thy-1 by Williams and colleagues indicated that it is a glycoprotein with a molecular weight of 17.5 kDa and 18.7 kDa in the brain and thymus, respectively. The Thy-1 molecule contains three N-linked oligosaccharides, which constitute about one-third of the mass of the molecule. Two of the N-linked glycans consist of complex-type oligosaccharides, while the third glycan consists of high-mannose oligosaccharides. The overall structure of the Thy-1 molecule resembles that of other members of the immunoglobulin superfamily. The Thy-1 and immunoglobulin molecules are similar in the position of the disulfide bonds, and in the high content of (3 sheet secondary structure with no a helices. The protein moiety of the Thy-1 molecule expressed on the surface of cells was found to consist of 111 amino acids in human and rat Thy-1 and of 112 amino acids in mouse Thy-1. In contrast, Silver demonstrated that the cDNA of Thy-1 codes for a Thy-1 molecule that should consist of 141-142 amino acids. The 31 amino acids beyond the carboxyl-cystein at position 111 were not expressed in most Thy-1 molecules. The missing stretch of amino acids contained a 26 amino acid sequence that is extremely hydrophobic, resembling the transmembrane segment found in many other membrane proteins. This apparent discrepancy became resolved when it was shown by Low and Kincade that most of the Thv-1 molecules do not penetrate through the cell membrane but rather are attached to a glycolipid on the cell membrane. It now seems that the entire 141-142 amino acid Thy-1 molecule is synthesized in the endoplasmic reticulum of the cell, is then cleaved off in position 111, and an amide linkage is formed between the carboxyl group on cysteine 1 I I and an ethanolamine amino group on a glycolipid precursor. The Thy-1 molecule, attached to glycolipid by a phosphatidylinositol (GPI) link is subsequently transported to the cell surface membrane, where it displays a distinct sensitivity to cleavage by phos-phatidylinositol-specific phospholipase C. Like other GPI-linked proteins, Thy-1 is localized in distinct membrane subdomains that are glycolipid enriched and detergent resistant. Immune precipitation of Thy-1 from nonionic detergent cell lysates of T cells coprecipitates the p56'li' and p60/v" sre family protein kinases.

What is the function of Thy-1? Although they lack a transmembrane domain, Thy-1 molecules are involved in the mitotic triggering of T lymphocytes. A brisk mitotic response can be elicited by xenogeneic antibodies against the Thy-1 antigen and by exposure to allogeneic monoclonal Thy-1 antibodies followed by xenogeneic anti-immunoglobulin antibodies. The crucial role of the Thy-1 molecule in the mitotic triggering by Thy-1 antibodies was established by the demonstration that transfection of lymphoid cells with the Thy-1 gene conferred upon them the capacity for a mitotic response to Thv-I antibodies. Protein kinases and possibly other accessory signaling molecules which are associated with Thy-1 molecules seem to be involved in the activation of T cells by Thy-1 antibodies.

Analysis of T cell mutants that have lost the expression of T cell receptors (TCRs) and experiments on the transfection of lymphocytes with the Thy-1 gene indicate that the TCR and particularly their £ chain, are necessary for effective mitotic stimulation of lymphocytes by Thy-1 antibodies. Indeed, stimulation via either Thy-1 or TCR may-proceed through a shared signaling pathway.

Rock and colleagues showed that T lymphocytes failed to be stimulated when they were coated with Thy-1 antibody and then exposed to anti-immunoglobulin antibodies bound to plastic. In contrast, exposure of T cells to antibodies against either TCR or the GD3 antigen, followed by exposure to immobilized anti-immunoglobulin antibodies resulted in mitotic stimulation. Thus, whereas cross-linking of the transmembrane molecular complex of the TCR suffices for mitotic stimulation, stimulation by Thy-1 may require entry of the molecules into the cell, possibly as a mechanism for communication with other components in the interior of the T cell.

In addition to regulating the mitotic triggering of T cells, Thy-1 molecules mediate intercellular attachment. Antibodies to Thy-1 inhibit the binding of mouse thymus cells to syngeneic erythrocytes, and interfere with the attachment of activated T lymphocytes to various nucleated target cells. He et al established that Thy-1 mediates the adhesion of thymocytes to thymic epithelial cells through a Ca2+-independent mechanism. In the nervous system, Thy-1 stabilizes neuronal connections and inhibits neurite outgrowth on astrocytes. The prevention of neurite outgrowth by Thy-1 molecules may reflect their role in mediating the adhesion between various cells within the nervous system.

See also: Alloantigens; Immunoglobulin gene super-family; Membrane-associated cytoskeleton: role in regulating immune cell function; Mouse inbred strains; Thymus; T lymphocyte activation; T lymphocytes.

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