B7-CD28 COSTIMULATION UNVEILS THE HIERARCHY OF TUMOR EPITOPES RECOGNIZED BY MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I-RESTRICTED CD8(-LYMPHOCYTES() CYTOLYTIC T)

Immunization of mice with tumors genetically engineered to express the B7 costimulatory molecules amplifies the antitumor immune response me diated by CD8(+) cytolytic T lymphocytes (CTL). In this report, we exa mined the effect of B7-CD28 costimulation on the hierarchy of tumor ep itopes. Using a combination of affinity chromatography/reversed-phase high performance liquid chromatography and CTL cloning, we show that m ajor histocompatibility complex (MHC) class I molecules from EL4 lymph oma cells can present at least six distinct CTL epitopes presented by MHC class I molecules. Nevertheless, mice immunized with wild-type B7- negative EL4 cells develop CTL only to one immunodominant epitope. In contrast, immunization with B7-transduced EL4 cells led to not only th e amplification of the CTL response to this immunodominant epitope, bu t also to the recognition of five otherwise silent subdominant epitope s. The adoptive transfer of a CTL clone against such a subdominant epi tope cured mice bearing EL4 lymphoma growing as an ascites tumor. The fact that CTL response can be spread to normally silent epitopes as a result of B7-CD28 costimulation suggests a novel approach to manipulat e the hierarchy of CTL epitopes and offers an opportunity to explore n ovel targets for T cell-mediated cancer therapy.