T-CELL TOLERANCE AND ACTIVATION TO A TRANSGENE-ENCODED TUMOR-ANTIGEN

Much has been learned in recent years concerning the nature of tumor a ntigens recognized by T cells. To apply this knowledge clinically the nature of the host response to individual and multiple tumor antigens has to he characterized. This will help to define the efficacy of immu ne surveillance and the immune status of the host following exposure t o tumor antigens expressed on pre-neoplastic tissue. To approach these questions, we have developed a transgenic mouse which expresses the t umor-specific antigen P91A. The single amino acid substitution in P91A results in the expression of a new MHC class I (H-2L(d))-binding pept ide. In transgenic tissue, the H-2L(d)/P91A complex is expressed in is olation from other tumor-associated antigens, allowing definition of t he immune response to a single defined tumor antigen, a situation clos ely analogous to events during tumorigenesis. We show that CD8(+) T ce ll immune surveillance of P91A is ineffective without the introduction of a helper determinant operating through stimulation of CD4(+) T cel ls. Recognition of the isolated P91A tumor antigen on normal tissue by CD8(+) T cells is a tolerogenic process. Induction of T cell toleranc e suggests tumor antigen-T cell interactions occurring during tumorige nesis may elicit T cell tolerance and hence confound some immunotherap eutic approaches.