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The timing of TGF-β inhibition affects the generation of antigen-specific CD8+ T Cells.
- Source :
- BMC Immunology; 2013, Vol. 14 Issue 1, p1-16, 16p, 1 Diagram, 1 Chart, 6 Graphs
- Publication Year :
- 2013
-
Abstract
- Background: Transforming growth factor (TGF)-β is a potent immunosuppressive cytokine necessary for cancer growth. Animal and human studies have shown that pharmacologic inhibition of TGF-β slows the growth rate of established tumors and occasionally eradicates them altogether. We observed, paradoxically, that inhibiting TGF-β before exposing animals to tumor cells increases tumor growth kinetics. We hypothesized that TGF-β is necessary for the anti-tumor effects of cytotoxic CD8<superscript>+</superscript> T lymphocytes (CTLs) during the early stages of tumor initiation. Methods: BALB/c mice were pretreated with a blocking soluble TGF-β receptor (sTGF-βR, TGF-β-blockade group, n=20) or IgG2a (Control group, n=20) before tumor inoculation. Tumor size was followed for 6 weeks. In vivo lymphocyte assays and depletion experiments were then performed to investigate the immunological basis of our results. Lastly, animals were pretreated with either sTGF-βR (n=6) or IgG2a (n=6) prior to immunization with an adenoviral vector encoding the human papillomavirus E7 gene (Ad.E7). One week later, flow cytometry was utilized to measure the number of splenic E7-specific CD8<superscript>+</superscript> T cells. Results: Inhibition of TGF-β before the injection of tumor cells resulted in significantly larger average tumor volumes on days 11, 17, 22, 26 and 32 post tumor-inoculation (p < 0.05). This effect was due to the inhibition of CTLs, as it was not present in mice with severe combined immunodeficiency (SCID) or those depleted of CD8<superscript>+</superscript> T cells. Furthermore, pretreatment with sTGF-βR inhibited tumor-specific CTL activity in a Winn Assay. Tumors grew to a much larger size when mixed with CD8<superscript>+</superscript> T cells from mice pretreated with sTGF-βR than when mixed with CD8<superscript>+</superscript> T cells from mice in the control group: 96 mm3 vs. 22.5 mm3, respectively (p < 0.05). In addition, fewer CD8<superscript>+</superscript> T cells were generated in Ad.E7-immunized mice pretreated with sTGF-βR than in mice from the control group: 0.6% total CD8<superscript>+</superscript> T cells vs. 1.9%, respectively (p < 0.05). Conclusions: These studies provide the first in vivo evidence that TGF-β may be necessary for anti-tumor immune responses in certain cancers. This finding has important implications for our understanding of anti-tumor immune responses, the role of TGF-β in the immune system, and the future development of TGF-β inhibiting drugs. [ABSTRACT FROM AUTHOR]
- Subjects :
- GROWTH factors
CYTOKINES
CELLULAR immunity
TUMORS
T cells
Subjects
Details
- Language :
- English
- ISSN :
- 14712172
- Volume :
- 14
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- BMC Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 89699410
- Full Text :
- https://doi.org/10.1186/1471-2172-14-30