Anti-CD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis
Anti-CD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis
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DOI：
10.1111/imm.12609
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发表时间：
2016-07-01
期刊：
影响因子：
6.4
通讯作者：
Fontenot, Jason D.
中科院分区：
文献类型：
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作者：
Huss, David J.;Pellerin, Alex F.;Fontenot, Jason D.
白细胞介素-2 （IL-2）通过其在T （Treg）细胞生物学中的非冗余作用，是免疫稳态的关键调节因子。在肿瘤免疫治疗中，通过调节IL-2通路来促进免疫激活，或在移植、自身免疫和炎症性疾病中增强免疫抑制，这是一个重要的研究方向。抗体介导的靶向高亲和力IL-2受体链（IL-2R或CD25）提供了靶向IL-2生物学的直接机制，目前正在临床中积极探索。在小鼠模型中，大鼠抗小鼠CD25克隆PC61被广泛用于研究IL-2和Treg细胞的生物学特性；然而，关于PC61在体内的确切机制功能一直存在争议和矛盾的数据。改变Fc/Fc受体相互作用的工程抗体可以显著改变其体内功能。在这项研究中，我们重新设计了抗cd25单克隆抗体的重链常数区，以产生具有高度发散Fc效应功能的变体。在多种小鼠模型中使用这些抗CD25 Fc变异体，我们研究了CD25阻断与CD25(+) Treg细胞消耗对免疫稳态的体内影响。我们报道，在CD25阻断期间免疫稳态可以维持，但当CD25(+) Treg细胞被主动耗尽时，异常t细胞激活普遍存在。这些结果阐明了PC61对Treg细胞生物学的影响，揭示了CD25阻断和CD25(+) Treg细胞耗竭之间的重要区别。这些发现应该为靶向高亲和力IL-2R的IL-2通路的治疗操作提供信息。
Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its non-redundant role in regulatory T (Treg) cell biology. There is major interest in therapeutic modulation of the IL-2 pathway to promote immune activation in the context of tumour immunotherapy or to enhance immune suppression in the context of transplantation, autoimmunity and inflammatory diseases. Antibody-mediated targeting of the high-affinity IL-2 receptor chain (IL-2R or CD25) offers a direct mechanism to target IL-2 biology and is being actively explored in the clinic. In mouse models, the rat anti-mouse CD25 clone PC61 has been used extensively to investigate the biology of IL-2 and Treg cells; however, there has been controversy and conflicting data on the exact in vivo mechanistic function of PC61. Engineering antibodies to alter Fc/Fc receptor interactions can significantly alter their in vivo function. In this study, we re-engineered the heavy chain constant region of an anti-CD25 monoclonal antibody to generate variants with highly divergent Fc effector function. Using these anti-CD25 Fc variants in multiple mouse models, we investigated the in vivo impact of CD25 blockade versus depletion of CD25(+) Treg cells on immune homeostasis. We report that immune homeostasis can be maintained during CD25 blockade but aberrant T-cell activation prevails when CD25(+) Treg cells are actively depleted. These results clarify the impact of PC61 on Treg cell biology and reveal an important distinction between CD25 blockade and depletion of CD25(+) Treg cells. These findings should inform therapeutic manipulation of the IL-2 pathway by targeting the high-affinity IL-2R.