Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4(+) T-regulatory cells and systemic collapse of antitumour immunity.
We investigated the relationship between transforming growth factor-beta (TGF-beta)-secreting T-regulatory (Tr) cells and anti-B16 melanoma immunity, and studied the association of early cytokines expressed at tumour sites with the generation of Tr cells. A large number of CD4(+) Tr cells producing interleukin (IL)-4, IL-10 and TGF-beta accumulated with functionally depressed CD8(+) cytotoxic T lymphocytes (CTLs) at tumour sites on day 20 after subcutaneous (s.c.) inoculation of B16 tumour cells. Tr cells consisted of two populations, which were termed T helper 3 (Th3) and Tr1 cells. B16-infiltrating Tr cells strongly inhibited the generation of B16-specific T helper 1 (Th1) cells in a TGF-beta-dependent manner and were assumed to suppress effective generation of CTLs. In addition, B16 cells markedly progressed in mice transferred adoptively by the cultured B16-infiltrating Tr cells compared with untreated mice. The capacity of these Tr cells to produce TGF-beta was hampered by neutralizing anti-IL-10 and partly anti-IL-4 monoclonal antibodies (mAbs) injected intralesionally during the early development of B16 tumours, and this treatment markedly attenuated B16 growth. Furthermore, a lesional injection of recombinant mouse IL-10 at an early tumour site resulted in the vigorous progression of B16 tumours. These results provide evidence that Tr cells, belonging to the T helper 3/T-regulatory 1 (Th3/Tr1) type, are activated in B16-bearing hosts under the influence of T helper 2 (Th2) cytokines, mainly IL-10 (produced at early tumour lesions), and that this regulatory T-cell population functions as a suppressor of anti-B16 immunity.
Seo
N
N
Department of Dermatology, Hamamatsu University School of Medicine, Shizuoka, Japan. seo445@hama-med.ac.jp
Hayakawa
S
S
Takigawa
M
M
Tokura
Y
Y
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018929:Cell Culture Techniques; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D007108:Immune Tolerance; D007111:Immunity, Cellular; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta; D016753:Interleukin-10