OBJECTIVES T cells play an essential role in controlling the development of B-cell lymphoproliferative disorders (BLPDs), but the dysfunction of T cells in BLPDs largely remains elusive. METHODS Using multiplexed flow cytometry, we quantified all major subsets of CD4+ helper T cells (Th) and CD8+ cytotoxic T cells (Tc) in 94 BLPD patients and 66 healthy controls. Statistics was utilised to rank T-cell signatures that distinguished BLPDs from healthy controls and differentially presented between indolent and aggressive categories. RESULTS By comparing with healthy controls, we found that the indolent but not aggressive type of BLPDs demonstrated a high degree of T-cell activation, showing the increase in type I helper T (Th1) cells and follicular B-helper T (Tfh) cells, both of which strongly associated with the enhanced differentiation of exhaustion-like effector cytotoxic CD8+ T cells expressing PD-1 (Tc exhaustion-like) in indolent BLPDs. Random forest modelling selected a module of T-cell immune signatures best performing binary classification of all BLPD patients. This signature module was composed of low naïve Th cells and high Th1, Tfh and Tc exhaustion-like cells which efficiently identified > 85% indolent cases and was, therefore, assigned as the Indolent Dominant Module of T-cell immune signature. In indolent BLPD patients, a strong bias towards such signatures was found to associate with clinical characteristics of worse prognosis. CONCLUSION Our study identified a prominent signature of T-cell dysregulation specifically for indolent BLPDs, suggesting Th1, Tfh and Tc exhaustion-like cells represent potential prognostic biomarkers and targets for immunotherapies.

中文翻译：

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T 细胞的显着免疫特征与惰性 B 细胞淋巴增生性疾病特别相关并预测预后。

目标 T 细胞在控制 B 细胞淋巴增殖性疾病 (BLPD) 的发展中发挥重要作用，但 BLPD 中 T 细胞的功能障碍在很大程度上仍然难以捉摸。方法 使用多重流式细胞术，我们量化了 94 名 BLPD 患者和 66 名健康对照者的 CD4+ 辅助 T 细胞 (Th) 和 CD8+ 细胞毒性 T 细胞 (Tc) 的所有主要亚群。利用统计数据对 T 细胞特征进行排序，这些特征将 BLPD 与健康对照区分开来，并在惰性和攻击性类别之间存在差异。结果 通过与健康对照比较，我们发现惰性但非侵袭性类型的 BLPD 表现出高度的 T 细胞活化，显示 I 型辅助 T (Th1) 细胞和滤泡 B 辅助 T (Tfh) 细胞增加, 两者都与惰性 BLPD 中表达 PD-1（Tc 衰竭样）的衰竭样效应细胞毒性 CD8+ T 细胞的增强分化密切相关。随机森林建模选择了一个对所有 BLPD 患者进行二元分类的最佳 T 细胞免疫特征模块。该特征模块由低初始 Th 细胞和高 Th1、Tfh 和 Tc 衰竭样细胞组成，可有效识别 > 85% 的惰性病例，因此被指定为 T 细胞免疫特征的惰性主导模块。在惰性 BLPD 患者中，发现对此类特征的强烈偏见与预后较差的临床特征相关。结论 我们的研究确定了 T 细胞失调的显着特征，特别是对于惰性 BLPD，提示 Th1，