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-like 2, one of these self-antigens. Experiments with Jalpha281-/- 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.
Nishikawa
Hiroyoshi
H
Second Department of Internal Medicine and Department of Bioregulation, Mie University School of Medicine, Mie 514-8507, Japan.
Kato
Takuma
T
Tawara
Isao
I
Takemitsu
Tetsushi
T
Saito
Kanako
K
Wang
Linan
L
Ikarashi
Yoshinori
Y
Wakasugi
Hiro
H
Nakayama
Toshinori
T
Taniguchi
Masaru
M
Kuribayashi
Kagemasa
K
Old
Lloyd J
LJ
Shiku
Hiroshi
H
D000818:Animals; D018949:Antigens, CD1 / Q000096:biosynthesis; D055610:Antigens, CD1d; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002273:Carcinogens; D049109:Cell Proliferation; D002860:Chromium Radioisotopes / Q000378:metabolism; D003001:Cloning, Molecular; D015536:Down-Regulation; D005260:Female; D005699:Galactosylceramides / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008297:Male; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013997:Time Factors
D018949:Antigens, CD1; D055610:Antigens, CD1d; D015704:CD4 Antigens; D002273:Carcinogens; D002860:Chromium Radioisotopes; D005699:Galactosylceramides; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; C493154:alpha-galactosylceramide; D008748:Methylcholanthrene