Coupling and uncoupling of tumor immunity and autoimmunity

Self-antigens, in the form of differentiation antigens, are commonly recogn ized by the immune system on melanoma and other cancers. We have shown prev iously that active immunization of mice against the melanocyte differentiat ion antigen, a tyrosinase-related protein (TRP) gp75(TRP-1) (the brown locu s protein) expressed by melanomas, could induce tumor immunity and autoimmu nity manifested as depigmentation. In this system, tumor immunity and autoi mmunity were mediated by autoantibodies. Here, we characterize immunity aga inst another tyrosinase family glycoprotein TRP-2 (the slaty locus protein) , using the same mouse model and method of immunization. As observed previo usly for gp75(TRP-1), immunity was induced by DNA immunization against a xe nogeneic form of TRP-2, but not against the syngeneic gene, and depended on CD4(+) cells. Immunization against TRP-2 induced autoantibodies and autore active cytotoxic T cells. In contrast to immunization against gp75(TRP-1), both tumor immunity and autoimmunity required CD8(+) T cells, but not antib odies. Only autoimmunity required perforin, whereas tumor immunity proceede d in the absence of perforin. Thus, immunity induced against two closely re lated autoantigens that are highly conserved through out vertebrate evoluti on involved qualitatively different mechanisms, i.e., antibody versus CD8T cell. However, both pathways led to tumor immunity and identical phenotyp ic man ifestations of autoimmunity.