Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK.
Immunity. 2013 Dec 12;39(6):1143-57. doi: 10.1016/j.immuni.2013.10.018. Epub 2013 Dec 5.
Complement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While "tonic" intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.
补体被视为先天免疫的关键血清作用成分，其关键成分 C3 的加工成激活片段 C3a 和 C3b 仅限于细胞外空间。我们在这里报告，C3 的激活也发生在细胞内。我们发现，T 细胞表达的蛋白酶组织蛋白酶 L (CTSL) 将 C3 加工成具有生物活性的 C3a 和 C3b。静止的 T 细胞含有大量的内体和溶酶体 C3 和 CTSL，以及大量 CTSL 生成的 C3a。虽然“基础”细胞内 C3a 的产生对于 T 细胞的存活是必需的，但 T 细胞刺激时这种细胞内 C3 激活系统向细胞表面的转运诱导了自分泌促炎细胞因子的产生。此外，自身免疫性关节炎患者的 T 细胞表现出过度活跃的细胞内补体激活和干扰素-γ产生，而 CTSL 抑制纠正了这种失调表型。重要的是，在所有检查的细胞群中都观察到细胞内 C3a，这表明细胞内补体激活可能具有广泛的生理意义。
