T-cell receptor transgenic analysis of tumor-specific CD8 and CD4 responses in the eradication of solid tumors

The role of tumor-specific CD8 and CD4 lymphocytes in rejecting solid tumor s has been difficult to determine because of the lack of models in which tu mor antigen, specific CD8 cells, and specific CD4 cells can be monitored an d controlled. To investigate the minimal components required for the induct ion and maintenance of CTL activity sufficient to reject a solid tumor in v ivo, we transfected the influenza hemagglutinin (HA) gene into a nonimmunog enic class I+/class II- murine malignant mesothelioma (MM) tumor line to ge nerate an endogenous tumor antigen and used TCR transgenic mice with class I- or class II-restricted specificities for HA as sources of naive, tumor-s pecific T cells. The data show that the presence of a strong tumor antigen is not in itself sufficient to induce an effective CTL response, nor does t he presence of a high frequency of precursor cells guarantee tumor rejectio n. We also show that tumor-specific CD4 cells, when CTL numbers are subopti mal, greatly enhance the eradication of tumor, confirming the importance of antigen-presenting cell presentation of tumor antigens to class II-restric ted cells. These data confirm that T-cell receptor transgenic cells, combin ed with nominal tumor antigen transfection, represent powerful tools to ana lyze tumor-specific T-cell responses.