PERIPHERAL T-CELL TOLERANCE AS A TUMOR ESCAPE MECHANISM - DELETION OFCD4(-CELLS SPECIFIC FOR A MONOCLONAL IMMUNOGLOBULIN IDIOTYPE SECRETEDBY A PLASMACYTOMA() T)

Tumors could escape an immune attack by inducing peripheral T cell tol erance. To test this, T cell receptor (TCR)-transgenic mice were injec ted with plasmacytoma cells secreting a highly tumor-specific antigen, a monoclonal immunglobulin (Ig), for which the transgene-encoded TCR is specific. The TCR recognizes a third hypervariable region idiotypic (Id) peptide of the Ig, presented by a class II molecule on host anti gen-presenting cells. The TCR-transgenic mice have previously been sho wn to be protected against an Id(+) plasmacytoma challenge. In the pre sent experiments, the protection was deliberately overwhelmed by subcu taneous injection of large numbers of plasmacytoma cells. Such tumor m ice, chronically exposed to increasing amounts of monoclonal Ig, delet e Id-specific CD4(+) T cells in their peripheral lymphoid organs and i n the tumor. The residual CD4(+) cells express endogenous, rather than transgene-encoded TCR alpha chains. Peripheral deletion, functional T cell unresponsiveness, and thymocyte deletion are all first detected at the same serum concentration of monoclonal Ig, similar to 50 mu g/m l (0.3 mu M), and become more acid more profound as the tumor burden i ncreases. The results suggest that peripheral T cell tolerance to Id c ould be a tumor escape mechanism in patients with B cell malignancies. In addition, the findings have implications for T cell tolerance to I g V regions in normal individuals.