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Abstract
Evidence for the essential role of regulatory T cells in maintaining immunological homeostasis comes from a range of in vitro and in vivo experimental systems, and naturally occurring regulatory T cells co-expressing CD4 and CD25 are of central interest with regard to the regulation of autoreactive T cells. A number of selfantigens are considered natural ligands for the maintenance of regulatory T cells while their molecular profiles are still elusive.
We have recently reported that immunization with serologically-defined broadly expressed selfantigens results in enhancement of pulmonary metastasis of i.v. challenged syngeneic transplantable tumor lines. These selfantigens were identified by serological identification of antigens by recombinant expression cloning (SEREX), a methodology widely used to identify immunogenic molecules in mice and human tumors. CD4+ CD25+ T cells obtained from mice immunized with SEREX-defined selfantigens had strong suppressive activity on peptide-specific proliferation of CD4+ CD25- T cells and CD8+ T cells. The suppressive effect was observed without in vitro T-cell stimulation. Foxp3 expression in these CD4+ CD25+ T cells from immunized mice was five to ten times greater than CD4+ CD25+ T cells derived from naive mice. Their in vitro suppressive activity essentially disappeared eight weeks after the last immunization. However, it was regained by in vitro restimulation with cognate selfantigen (Dna J-like 2) protein but not with control protein. We propose that SEREX-defined selfantigens such as those used in this study represent selfantigens that elicit naturally occurring CD4+ CD25+ regulatory T cells.
We also 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-defined selfantigens resulted in acceleration of tumor development. 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 Dna J-like 2, one of these selfantigens. Experiments with J(alpha)281-/- mice lacking NKT cells indicated that NKT cells responsible for regulating the development of MCA-induced tumors were suppressed in immunized hosts. We propose that CD4+ CD25+ regulatory T cells generated by immunization with these selfantigens enhance susceptibility to MCA induced-tumorigenesis by controlling NKT reactivity, and suggest that these observations are the strong evidence for the existence of cancer immunosurveillance in this system of chemical carcinogenesis.
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