Transforming growth factor-beta1 suppresses interleukin-15-mediated interferon-gamma production in human T lymphocytes.
One of the most remarkable means by which tumour cells manage to evade recognition and elimination by the immune system is the release of immunosuppressive mediators, such as interleukin (IL)-10 or transforming growth factor-beta (TGF-beta). For antitumour immunotherapies to reach their full potential, cytokine cocktails will have to be custom-tailored to the tumour's individual cytokine microenvironment. One of the components of such a cytokine cocktail may be interleukin (IL)-15, which has demonstrated an excellent stimulatory potential of antitumour immunity. In an in vitro model, we have previously been able to show that the negative effects of IL-10 on IL-15-mediated cytotoxic T-cell activation can be outweighed by the addition of interleukin (IL)-12. The mechanism by which TGF-beta may influence the effect of IL-15 remains poorly understood, however. We have therefore taken our T-cell model further and have studied the effect of TGF-beta on IL-15-mediated interferon-gamma (IFN-gamma) production. In activated, IL-15-stimulated peripheral blood T lymphocytes, TGF-beta suppressed IFN-gamma mRNA and protein levels by approximately 75%. This effect was likewise observed on both CD4+ and CD8+ T cells and, in contrast to the effect of IL-10 in this system, could not be neutralized by the addition of IL-12. Thus, immunotherapy for TGF-beta-producing tumours may benefit from the addition of TGF-neutralizing activity rather than IL-12.
Bönig
H
H
Laboratory of Experimental Hematology and Stem Cell Transplantation, Department of Pediatric Hematology and Oncology, Heinrich-Heine-University Medical Center, Düsseldorf, Germany.
Banning
U
U
Hannen
M
M
Kim
Y M
YM
Verheyen
J
J
Mauz-Körholz
C
C
Körholz
D
D
D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003864:Depression, Chemical; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D016753:Interleukin-10 / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D019409:Interleukin-15 / Q000037:antagonists & inhibitors*; D007376:Interleukin-2 / Q000494:pharmacology; D016853:Muromonab-CD3 / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D019409:Interleukin-15; D007376:Interleukin-2; D016853:Muromonab-CD3; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma