Authentic GITR Signaling Fails To Induce Tumor Regression unless Foxp3+ Regulatory T Cells Are Depleted
Authentic GITR Signaling Fails To Induce Tumor Regression unless Foxp3+ Regulatory T Cells Are Depleted
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DOI：
10.4049/jimmunol.1403076
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发表时间：
2015-11-15
影响因子：
4.4
通讯作者：
Kwon, Byoung S.
中科院分区：
文献类型：
--
作者：
Kim, Young H.;Shin, Su M.;Kwon, Byoung S.
糖皮质激素诱导的TNFR家族相关蛋白（GITR, TNFRSF18, CD357）在效应和调节性T （Treg）细胞上表达。先前的研究表明，抗GITR单抗触发GITR可增强T细胞和B细胞介导的免疫应答。然而，gitr缺陷的T细胞也比正常的T细胞增殖更多，这种影响是无法解释的。由于单克隆抗体的活性受其Fc区控制，因此需要通过检查其与真实配体的相互作用来确定GITR信号的真实效果。因此，我们生成了一种五聚体形式的GITRL细胞外结构域（pgirl），用于连接GITR，并将其与抗GITR单抗对T细胞的作用进行了比较。gitrl在体外和体内均比anti-GITR mAb更有效地促进效应细胞和调节细胞的增殖。尽管如此，pGITRL在体内仅抑制MC38腺癌细胞的生长最初15 d，而抗gitr单抗则无限期地抑制MC38腺癌细胞的生长。详细分析表明，ppgitrl诱导Foxp3(+)CD4(+) Treg细胞广泛增殖，导致活化的Treg细胞在肿瘤组织和引流淋巴结中积累。由于GITR信号不能中和活化的Treg细胞的抑制活性，当足够的活化的Treg细胞在淋巴结和肿瘤组织中积累时，pitrl似乎失去了辅助作用。事实上，ppgitrl的抗肿瘤作用通过消耗CD4（+）细胞而显著增强。这些结果表明GITR信号对效应T细胞具有刺激作用，并通过Treg细胞具有抑制作用。
The glucocorticoid-induced TNFR family-related protein (GITR, TNFRSF18, CD357) is expressed on effector and regulatory T (Treg) cells. Previous studies demonstrated that GITR triggering by anti-GITR mAb enhanced T and B cell-mediated immune responses. GITR-deficient T cells, however, also proliferate more than normal T cells, and this effect is unexplained. Because the activities of mAbs are controlled by their Fc regions, the true effect of GITR signaling needs to be determined by examining its interaction with authentic ligand. Therefore, we generated a pentamerized form of the GITRL extracellular domain (pGITRL) for ligation to GITR and compared its effect on T cells with that of anti-GITR mAb. The pGITRL was more effective than anti-GITR mAb in enhancing the proliferation of effector and regulatory cells in vitro and in vivo. Nonetheless, the growth of MC38 adenocarcinoma cells in vivo was only suppressed for initial 15 d by pGITRL, whereas it was suppressed indefinitely by anti-GITR mAb. Detailed analysis revealed that pGITRL induced extensive proliferation of Foxp3(+)CD4(+) Treg cells and led to the accumulation of activated Treg cells in tumor tissue and draining lymph nodes. Because GITR signaling could not neutralize the suppressive activity of activated Treg cells, pGITRL seems to lose its adjuvant effect when sufficient activated Treg cells have accumulated in the lymph nodes and tumor tissue. Indeed, the antitumor effects of pGITRL were markedly enhanced by depleting CD4(+) cells. These results suggest that GITR signaling has stimulatory effects on effector T cells and inhibitory effects through Treg cells.