Transforming growth factor-beta (TGF-beta)-mediated immunosuppression in the tumor-bearing state: enhanced production of TGF-beta and a progressive increase in TGF-beta susceptibility of anti-tumor CD4+ T cell function.
The present study deals with the effect of transforming growth factor-beta (TGF-beta) on anti-tumor immune responsiveness at various stages of the tumor-bearing state. Spleen cells from BALB/c mice bearing a syngeneic tumor (CSA1M) 1-3 wk after inoculation with CSA1M cells produced interleukin-2 (IL-2) and macrophage-activating factor (MAF)/interferon-gamma (IFN-gamma) upon in vitro culture without addition of exogenous tumor antigens. This lymphokine production was achieved through collaboration between anti-CSA1M CD4+ T cells and antigen-presenting cells that had been pulsed with CSA1M tumor antigens in vivo in the tumor-bearing state. The IL-2-producing capacity of CD4+ T cells reached the maximal level as early as one week after tumor implantation but decreased with the progress of tumor-bearing stages. In contrast, the capacity of CD4+ T cells to produce MAF/IFN-gamma was not affected but was maintained at high levels even late in the tumor-bearing state. The addition of recombinant TGF-beta (rTGF-beta) to cultures of spleen cells from various tumor-bearing stages resulted in the suppression of lymphokine production. However, the magnitude of the TGF-beta-induced suppression varied depending on which tumor-bearing stages of splenic cells were tested as a responding cell population; it was slight in cells from early (1-3 wk) tumor-bearing stages but increased in cells from donor mice at later tumor-bearing stages. Thus, spleen cells from late tumor-bearing stages with weak but significant IL-2-producing and considerable MAF/IFN-gamma producing capacities failed to produce these lymphokines when rTGF-beta was present in cultures. A progressive increase in the TGF-beta susceptibility was also observed for IL-4-producing Th2 as well as IL-2/MAF-producing Th1 cells. In addition, increased levels of TGF-beta were detected in plasma from tumor-bearing mice at late stages. Taken together, these results indicate that tumor-bearing mice exhibit enhanced production of TGF-beta as well as a progressive increase in the susceptibility of anti-tumor CD4+ T cells to TGF-beta-induced suppressive mechanisms.
Li
X F
XF
Biomedical Research Center, Osaka University Medical School.
Takiuchi
H
H
Zou
J P
JP
Katagiri
T
T
Yamamoto
N
N
Nagata
T
T
Ono
S
S
Fujiwara
H
H
Hamaoka
T
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005354:Fibrosarcoma / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D016215:Macrophage-Activating Factors / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D016215:Macrophage-Activating Factors; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma