Immune surveillance depends in part on the recognition of peptide variants by T cell antigen receptors. Given that both normal B cells and malignant B cells accumulate mutations we chose a murine model of multiple myeloma to test conditions to induce cell-mediated immunity targeting malignant plasma cell (PC) clones but sparing of normal PCs. Revealing a previously unknown function for intracellular C3d, we found that C3d engaged T cell responses against malignant PC in the bone marrow of mice that had developed multiple myeloma spontaneously. Our results show that C3d internalized by cells augments immune surveillance by several mechanisms. In one, C3d induces a master transcription regulator, E2f1, to increase the expression of long noncoding (lnc) RNAs, to generate peptides for MHC-I presentation, and increase MHC-I expression. In another, C3d increases expression of RNAs encoding ribosomal proteins linked to processing of defective ribosomal products that arise from noncanonical translation and known to promote immunosurveillance. Cancer cells are uniquely susceptible to increased expression and presentation of mutant peptides given the extent of protein misfolding and accumulation of somatic mutations. Accordingly, although C3d can be internalized by any cell, C3d preferentially targets malignant clones by evoking specific T cell–mediated immunity and sparing most nontransformed polyclonal B cells and PC with lower mutation loads. Malignant PC deletion was blocked by cyclosporin or by CD8 depletion confirming that endogenous T cells mediated malignant clone clearance. Besides the potential for therapeutic application our results highlight how intracellular C3d modifies cellular metabolism to augment immune surveillance.

中文翻译：

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补体 C3d 使细胞介导的免疫能够区分自发转化的细胞和未转化的细胞


免疫监视部分取决于 T 细胞抗原受体对肽变体的识别。鉴于正常 B 细胞和恶性 B 细胞都会积累突变，我们选择了多发性骨髓瘤的小鼠模型来测试诱导细胞介导的免疫的条件，靶向恶性浆细胞 （PC） 克隆，但保留正常 PC。揭示了细胞内 C3d 以前未知的功能，我们发现 C3d 参与 T 细胞反应对自发发展为多发性骨髓瘤的小鼠骨髓中的恶性 PC。我们的结果表明，细胞内化的 C3d 通过多种机制增强免疫监视。在一种研究中，C3d 诱导主转录调节因子 E2f1 增加长链非编码 （lnc） RNA 的表达，产生用于 MHC-I 呈递的肽，并增加 MHC-I 表达。在另一种研究中，C3d 增加了编码核糖体蛋白的 RNA 的表达，这些蛋白与非经典翻译产生的缺陷核糖体产物的加工有关，并且已知可促进免疫监视。鉴于蛋白质错误折叠和体细胞突变积累的程度，癌细胞特别容易受到突变肽表达和呈递增加的影响。因此，尽管 C3d 可以被任何细胞内化，但 C3d 通过诱发特异性 T 细胞介导的免疫并保留大多数未转化的多克隆 B 细胞和突变负荷较低的 PC，优先靶向恶性克隆。恶性 PC 缺失被环孢菌素或 CD8 耗竭阻断，证实内源性 T 细胞介导了恶性克隆清除。除了治疗应用的潜力外，我们的结果还强调了细胞内 C3d 如何改变细胞代谢以增强免疫监视。