Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts

We examined the role of CD4(+)CD25(+) regulatory T cells in the development of 3-methylcholanthrene (MCA)-induced tumors. Immunization of wild-type BALB/c mice with a series of SEREX (serological identification of antigens by recombinant expression cloning)defined broadly expressed self-antigens results in the development of highly active CD4(+)CD25(+) regulatory T cells. Accelerated tumor development was observed in mice immunized with self-antigens and was abolished by antibody-mediated depletion of CD4(+) T cells or CD25(+) T cells. A similar acceleration of tumorigenesis was also observed in mice adoptively transferred 2 or 4 weeks after MCA injection with CD4(+)CD25(+) T cells derived from mice immunized with DnaJ-Iike 2, one of these self-antigens. Experiments with J alpha 281(-/-) mice lacking invariant natural killer (iNK) T cells indicated that iNK T cells, known for their protective role in the development of MCA-induced tumors, were suppressed in immunized hosts. NK cells, also known to play a protective role in MCA induced-tumorigenesis, were also suppressed in mice immunized with serologically defined self-antigens in a CD4(+)CD25(+) T cell-dependent manner. We propose that CD4(+)CD25(+) regulatory T cells generated by immunization with these self-antigens enhance susceptibility to MCA induced-tumorigenesis by down-regulating iNK T and NK reactivity, and suggest that these observations provide direct evidence for the existence of cancer immunosurveillance in this system of chemical carcinogenesis.