ANTIGEN RECOGNITION AND ALLOGENEIC-TUMOR REJECTION IN CD8(+) TCR TRANSGENIC RAG(-/-) MICE/

Three sources of help for the development of a CD8(+) CTL response hav e been described: the CD4(+) direct and indirect pathways and the CD8( +) direct pathway. In an effort to understand the minimal requirements for the development of a CTL response in vivo, we have bred mice tran sgenic for the 2C TCR onto a RAG(-/-) background. The 2C T cells in th is animal are exclusively CD8(+) CTLs of a single specificity, and the y exhibit altered thymic maturation compared with that of T cells from 2C TCR/RAG(+/+) mice. T cells from 2C TCR/RAG(-/-) mice can be activa ted to a high level in vivo by administration of a self-MHC-restricted antigenic peptide. The 2C TCR/RAG(-/-) mice are able to reject B7-neg ative allogeneic tumors bearing the appropriate peptide/MHC ligand p2C /L-d. These mice fail to reject syngeneic tumors, and their RAG(-/-) l ittermates lacking 2C T cells uniformly succumb to both allogeneic and syngeneic tumors. Moreover, blockade of B7 costimulatory molecules fa ils to prevent tumor rejection in the 2C TCR/RAG(-/-) mice, suggesting that allorejection is occurring independently of B7-mediated costimul ation as well as in the absence of CD4(+) T cells. CTLs isolated from the site of the tumor during the period of rejection express the activ ation marker CD25 and are able to mediate ex vivo cytolysis of tumor c ells bearing the appropriate Ag. These results suggest that in this TC R transgenic model with a very high precursor frequency, CTL developme nt can occur in the absence of B7:CD28 costimulation and without CD4() help.