Triggering of OX40 (CD134) on CD4+CD25+ T cells blocks their inhibitory activity:: a novel regulatory role for OX40 and its comparison with GITR
Triggering of OX40 (CD134) on CD4+CD25+ T cells blocks their inhibitory activity:: a novel regulatory role for OX40 and its comparison with GITR
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DOI：
10.1182/blood-2004-07-2959
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发表时间：
2005-04-01
期刊：
影响因子：
20.3
通讯作者：
Colombo, MP
中科院分区：
文献类型：
--
作者：
Valzasina, B;Guiducci, C;Colombo, MP
OX40 （CD134）是肿瘤坏死因子（TNF）受体家族的一员，在T细胞受体（TCR）结扎后在T细胞上短暂表达。初始和激活的CD4(+)CD25（+）调节性T细胞（T reg’s）都表达OX40，但其功能作用尚未确定。由于糖皮质激素诱导的肿瘤坏死因子受体（GITR）是TNF受体家族的相关成员，影响T reg功能，我们测试了OX40是否有类似的作用。使用激动剂抗体触发T regs上的GITR或OX40抑制了它们抑制和恢复效应T细胞增殖、白细胞介素-2 （IL-2）基因转录和细胞因子产生的能力。在移植物抗宿主病（GVHD）模型中证实了OX40消除T reg抑制的作用。在完全同种异体C57BL/6 > BALB/c骨髓移植中，除非T细胞与骨髓和效应T细胞共转移，否则GVHD是致命的。引人注目的是，通过在移植后立即腹腔注射抗ox40或抗gitr单克隆抗体（mab），或在移植前用相同的单克隆抗体体外预处理T reg，可以消除T reg对GVHD的抑制作用。结果表明，OX40除了控制记忆T细胞数量外，还直接控制T reg介导的抑制。
OX40 (CD134) is a member of the tumor necrosis factor (TNF) receptor family that is transiently expressed on T cells after T-cell receptor (TCR) ligation. Both naive and activated CD4(+)CD25(+) regulatory T cells (T reg's) express OX40 but its functional role has not been determined. Since glucocorticoid-induced tumor necrosis factor receptor (GITR), a related TNF receptor family member, influences T reg function, we tested whether OX40 might have similar effect. Triggering either GITR or OX40 on T reg's using agonist antibodies inhibited their capacity to suppress and restored effector T-cell proliferation, interleukin-2 (IL-2) gene transcription and cytokine production. OX40 abrogation of T reg suppression was confirmed in vivo in a model of graft-versus-host disease (GVHD). In a fully allogeneic C57BL/6 > BALB/c bone marrow transplantation, GVHD was lethal unless T reg's were cotransferred with the bone marrow and effector T cells. Strikingly, T reg suppression of GVHD was abrogated either by intraperitoneal injection of anti-OX40 or anti-GITR monoclonal antibodies (mAbs) immediately after transfer, or by in vitro pretreatment of T reg's with the same mAbs before transfer. Cumulatively, the results suggest that in addition to controlling memory T-cell numbers, OX40 directly controls T reg-mediated suppression.