期刊
JOURNAL OF IMMUNOTHERAPY
卷 32, 期 8, 页码 793-802出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e3181acec1e
关键词
VLA-4; VLA-6; IL-4; T helper-1; melanoma
资金
- NATIONAL CANCER INSTITUTE [P01CA100327, P01CA101944, R01CA063350] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS055140] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA063350-10, R01 CA063350, P01 CA100327, R01 CA63350, P01 CA101944] Funding Source: Medline
- NINDS NIH HHS [R01 NS055140-02, R01NS055140, R01 NS055140] Funding Source: Medline
Murine CD4(+) T cells cultured under type I polarizing conditions selectively express significantly higher levels of the very late antigen (VLA)-4 and VLA-6 integrins when compared with T cells cultured under type 2 or nonpolarizing (type 0) conditions. This difference appears due to the action of interleukin (IL)-4, as loss of VLA-4/-6 expression on Th cells was prevented by inclusion of neutralizing anti-IL-4 mAb during the initial culture period. We also observed that CD4(+) T cells deficient in Stat6, a critical component of the IL-4R signaling cascade, retained high levels of VLA-4 and VLA-6 expression, regardless of IL-4 status in the culture conditions. When applied to committed Th1 cells, rIL-4 readily inhibited VLA-4 and VLA-6 expression to levels observed for Th2 cells, without altering the type I functional status of these cells. Conversely, low levels of VLA-4/VLA-6 expressed by committed Th2 cells could not be resurrected by culture in the presence of the Th1-kines IL-12p70 and interferon-gamma. Predictably, among the Th populations evaluated, Th1 cells alone adhered efficiently to, and were costimulated by, plate-bound VCAM-I and laminin in a VLA-4-dependent or VLA-6-dependent manner, respectively. Finally, adoptive-transferred Th1 (but not Th2) cells developed from OT-II mice were uniquely competent to traffick into OVA(+) M05 melanoma lesions in vivo, thereby enhancing the therapeutic benefits associated with cotransferred OVA-specific type I CD8(+) (OT-I) cells. These data suggest that treatment strategies capable of sustaining/enhancing VLA-4/VLA-6 expression on Th I effector cells may yield improved clinical efficacy in the cancer setting.
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