Role of STAT3 in CD4+CD25+FOXP3+ regulatory lymphocyte generation:: Implications in graft-versus-host disease and antitumor immunity
Role of STAT3 in CD4+CD25+FOXP3+ regulatory lymphocyte generation:: Implications in graft-versus-host disease and antitumor immunity
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DOI：
10.4049/jimmunol.179.11.7593
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Borg, Christophe
中科院分区：
文献类型：
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作者：
Pallandre, Jean-Rene;Brillard, Emilie;Borg, Christophe
免疫耐受性由包括CD 4（+）CD 25（+）FOXP 3（+）调节细胞（Treg）在内的特化T细胞亚群维持。先前的研究证实Treg胸腺分化或外周转化依赖于CD 28和Lck信号传导。此外，鼠CD 4（+）CD 25（-）T淋巴细胞中的foxp 3基因转移导致获得抑制功能。然而，导致FOXP 3表达的分子途径仍有待描述。在这项研究中，我们研究了驱动FOXP 3表达的分子事件。我们证明了CD 4（+）CD 25（-）T淋巴细胞中的CD 28活化以Lck依赖性方式导致STAT 3 Tyr 705磷酸化。通过TCR/CD 28和TGF-β 1的共刺激，在幼稚外周CD 4（+）CD 25（-）T细胞转化为Treg期间，STAT 3中和降低了FOXP 3表达，阻止了抑制功能的获得，并恢复了转化的淋巴细胞产生IL-2和IFN-γ的能力。此外，我们观察到使用小干扰RNA策略的STAT 3消融抑制了自然分化的CD 4（+）CD 25（+）T淋巴细胞中的FOXP 3表达和抑制功能，表明STAT 3在Treg表型和功能维持中的直接作用。用特异性STAT 3小干扰RNA转导的CD 4（+）CD 25（+）T淋巴细胞缺乏抑制功能，不能控制急性移植物抗宿主病的发生。最后，抑制CD 4（+）淋巴细胞中的STAT 3增强了淋巴细胞过继转移所赋予的抗肿瘤免疫力。总之，我们的研究结果确定STAT 3在FOXP 3表达所需的分子途径中至关重要。在评估调节性T细胞如何促进炎症性疾病和肿瘤免疫监视时，应考虑STAT 3调节。
Immunological tolerance is maintained by specialized subsets of T cells including CD4(+)CD25(+)FOXP3(+) regulatory cells (Treg). Previous studies established that Treg thymic differentiation or peripheral conversion depend on CD28 and Lck signaling. Moreover, foxp3 gene transfer in murine CD4(+)CD25(-) T lymphocytes results in the acquisition of suppressive functions. However, molecular pathways leading to FOXP3 expression remain to be described. In this study, we investigated the molecular events driving FOXP3 expression. We demonstrated that CD28 activation in CD4(+)CD25(-) T lymphocytes leads to STAT3 Tyr 705 phosphorylation in an Lck-dependent manner. STAT3 neutralization during naive peripheral CD4(+)CD25(-) T cell conversion into Treg through costimulation with TCR/CD28 and TGF-beta 1, decreased FOXP3 expression, prevented the acquisition of suppressive functions and restored the ability of the converted lymphocytes to produce IL-2 and IFN-gamma. Furthermore, we observed that STAT3 ablation using small interfering RNA strategies inhibited FOXP3 expression and suppressive functions among naturally differentiated CD4(+)CD25(+) T lymphocytes, suggesting a direct role of STAT3 in Treg phenotype and function maintenance. CD4(+)CD25(+) T lymphocytes transduced with specific STAT3 small interfering RNA were devoid of suppressive functions and failed to control the occurrence of acute graft-vs-host disease. Finally, STAT3 inhibition in CD4(+) lymphocytes enhanced the anti-tumor immunity conferred by a lymphocyte adoptive transfer. In summary, our findings determine that STAT3 is critical in the molecular pathway required for FOXP3 expression. STAT3 modulation should be taken into account when assessing how regulatory T cells contribute to inflammatory diseases and tumor immunosurveillance.