期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 38, 期 10, 页码 2865-2873出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/eji.200838334
关键词
Adoptive therapy; IL-4; Melanoma; Tc1; VLA-4
类别
资金
- National Institutes of Health (NIH) [R01 CA63350, R01 NS055140]
We and others have previously demonstrated that IL-4-dependent Tc2 are inferior to Tc1-effector CD8(+) T cells in regulating tumor progression in vivo. This functional disparity relates, in part, to the comparatively poor ability of Tc2 to migrate into diseased tissues. We now show that IL-4 treatment of committed Tc1 cells promotes the selective loss in the expression of very-late antigen (VLA)-4, without impacting the Tc1 cytokine production profile, cytotoxic activity, or expression of alternate cell surface markers. Down-regulation of VLA-4 expression on Tc1 cells was unique to treatment with IL-4 (i.e. Tc1(IL-4)) and did not occur in the presence of the Type-2 cytokine IL-13 or the regulatory cytokines IL-10 or TGF-beta. Notably, the inhibitory effects of IL-4 on Tc1 expression of VLA-4 could be blocked by the presence of IL-12, but not IFN-gamma. Predictably, Tc1(IL-4) (but not Tc1 control) cells adhere poorly to plate-bound VCAM-1-Fc fusion protein and fail to be co-stimulated by VCAM-1 in vitro. They were also markedly impaired in their ability to traffic into intracranial melanoma lesions after adoptive transfer, yielding inferior therapeutic benefit to tumor-bearing mice. These results suggest a novel suppressive mechanism for IL-4 that limits Tc1 efficacy via preventing their recruitment into tumors.
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