The histocompatibility or transplantation antigens are cell-surface glycoproteins that are present on nearly all vertebrate cells but appear in greatest amounts on lymphocytes (Klein 1975). They display an unusually extensive genetic polymorphism, and their function may be intimately connected with the immune response (Ir). Studies of the structure of human (HL-A) and mouse (H-2) major histocompatibility antigens indicate that they are closely associated with β2-microglobulin (Nakamuro et al. 1973; Peterson et al. 1974; Silver and Hood 1974), a protein that has sequence homology with the immunoglobulins (Peterson et al. 1972; Cunningham et al. 1973). This finding is in accord with hypotheses (Burnet 1970; Gaily and Edelman 1972) that the immune system and histocompatibility system may have a common evolutionary origin and that they may share some similar effector functions.

H-2 alloantisera have been previously reported to contain antibodies against murine leukemia viral antigens, but the nature of the viral antigens on mouse cells which interact with these antibodies has not been established. We have found that H-2 alloantisera recognize components of molecular weight 70 000-80 000 mouse lymphocytes and leukemia cells. These components were also detected by a goat antiserum against the murine leukemia virus (MuLV) glycoprotein (gp 70) and are therefore closely related to or identical with that viral protein. Although most H-2 alloantisera detected gp 70-like molecules on lymphocytes and leukemia cells from a great variety of mouse strains, only one H-2 alloantiserum was found to interact with a gp 70 component on cells from C57BL/10 and C57BL/6 mice. Animals such as C57BL/10 mice that lacked the component reacting with most H-2 alloantisera showed increased serum levels of anti-MuLV antibodies after injection of B10.A spleen cells having a gp 70 component detectable by other H-2 alloantisera. In contrast, strains with cells reactive to antiviral antibodies in the H-2 alloantisera had low responses to MuLV antigens after a similar immunization procedure. Serum levels of anti-MuLV antibodies in both groups of mice, however, were increased after injection of Freund's adjuvant. These observations suggest that anti-MuLV antibodies in mouse alloantisera may arise from a response to viral antigens on the immunizing cells and general stimulation of the immune system.

Detergent and papain solubilized murine histocompatibility (H-2) antigens have been compared by gel exclusion chromatography, ultracentrifugation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and amino-acid sequence analysis. From these data, we propose a molecular model for the H-2 antigens that includes the size and arrangement of the subunits on the cell surface and in solution, and we provide evidence for the orientation of these molecules on the cell surface. Detergent solubilized H-2 antigens (molecular weight 116,000) consist of two disulfide-linked heavy chains (46,000 daltons) and two monocovalently associated light chains (12,000 daltons). Alkylation with iodoacetamide prior to extraction prevented the formation of a disulfide linkage between the two heavy chains. A water-soluble 51,000-dalton molecule (Fs) consisting of a 39,000-dalton fragment (FH) of the heavy chain and one intact light chain was obtained by papain digestion of cells or detergent extracts. Therefore, the disulfide linkage between the heavy chains is located in the remaining membrane-associated portion (Fm). Amino-acid sequence analysis of the FH fragment of H-2Kb by radiochemical techniques showed that it is identical to the detergent solubilized H-2Kb heavy chain in eight positions for the three amino acids tested. These data indicate that the fragment FH derives from the amino-terminus of the heavy chain and suggest that it projects outward from the cell surface, while the carboxyl-terminal region is associated with the plasma membrane. The described amino-terminal sequence data have been found constant in H-2Kb, H-2Kd, H-2Kk, H-2Db, and H-2Dd gene products. These data support the hypothesis that the K and D products of the major histocompatibility antigen complex have evolved by gene duplication.

Physico–chemical studies and amino acid sequence analysis of H–2 antigens have provided a working model of these molecules that includes the size and arrangement of the subunits on the cell surface and in solution and the orientation of the molecules on the cell surface. Comparisons of the partial amino acid sequences of H–2Kb,H–2Kd, H–2Kk, H–2Db, and H–2Dd gene products support the hypothesis that the K and D loci evolved by gene duplication. A variety of evidence indicates that H–2 antigens can be physically associated with viral antigens on the cell and we have found that H–2 and viral antigens can co-cap and co-patch on the cell surface. We suggest that one function of H–2 antigens is to serve as adaptors that combine with foreign antigens to form hybrid antigens, which are recognized by cytotoxic T lymphocytes.

Histocompatibility antigens are glycoproteins found on the surface membranes of vertebrate cells. The significance of these antigens in the rejection of allografts between individuals has been well established (1), and the genetics of these polymorphic systems have been studied in detail in the mouse (H-2) and in man (HL-A). The segment of the 17th chromosome of the mouse containing the major histocompatibility complex is shown in Figure 1. Despite all the information available regarding these molecules, the physiological function of H-2 and HL-A antigen is not known. A number of studies has shown that histocompatibility antigens are involved in cell-mediated lysis of xenoor allogeneic cells (2, 3). Recently it has been observed that murine histocompatibility antigens participate in the lysis of syngeneic chemically modified cells (4), virally infected cells (5) and neo-plastic cells (6, 7, 8). These data support the notion that histocompatibility antigens play an important role in the elimination of antigenically abnormal cells, and thus, they may form a highly complicated system of membrane proteins that serve as signals to distinguish “self” from “non-self”.