BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion.
BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion.
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BCL-2表达通过增强调节性T细胞分化和细胞毒性T细胞耗竭促进慢性淋巴细胞白血病的免疫抑制。
DOI：
10.1186/s12943-022-01516-w
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发表时间：
2022-02-22
期刊：
影响因子：
37.3
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Liu L;Cheng X;Yang H;Lian S;Jiang Y;Liang J;Chen X;Mo S;Shi Y;Zhao S;Li J;Jiang R;Yang DH;Wu Y
慢性淋巴细胞白血病（CLL）导致对感染的易感性增加。并非所有患者的T细胞功能障碍与CLL相关；因此，鉴别有T细胞缺陷的CLL患者是很重要的。b细胞淋巴瘤-2 （BCL-2）在CLL中的作用已被探讨；然而，很少有研究检测其在CLL患者T细胞中的作用。在此，我们研究了BCL-2在CLL肿瘤微环境中对T细胞的调节作用。流式细胞术检测BCL-2在T细胞中的表达。利用单细胞RNA测序（scRNA-seq）研究BCL-2的调控作用，并利用多参数流式细胞术对CD4和CD8 T细胞进行验证。探讨了CLL患者T细胞中BCL-2表达的临床特点。我们发现CLL患者T细胞中BCL-2表达显著升高（n = 266）。单细胞RNA测序（scRNA-seq）显示BCL-2+CD4+ T细胞具有调节性T细胞（Treg）增加的基因特征；BCL-2+CD8+ T细胞表现出衰竭细胞毒性T淋巴细胞（CTL）的基因特征；BCL-2表达增加与T细胞活化和细胞粘附有关。scRNA-seq结果在70例CLL患者的外周血T细胞中得到验证，BCL-2+CD4+ T细胞富集Tregs，白细胞介素-10和转化生长因子-β的表达高于BCL-2 - CD4+ T细胞。BCL-2在CD8+T细胞中的表达与衰竭细胞（PD-1+Tim-3+）以及颗粒酶B和穿孔素的弱表达相关。T细胞相关细胞因子分析显示BCL-2+ T细胞与T细胞活化之间呈负相关。在venetoclax治疗后完全缓解的CLL患者中，观察到BCL-2+T细胞的频率和恢复功能下降。CLL患者T细胞中BCL-2的表达通过促进Treg丰度和CTL衰竭与免疫抑制有关。在线版本包含补充材料，可在10.1186/s12943-022-01516-w获得。
Chronic lymphocytic leukemia (CLL) results in increased susceptibility to infections. T cell dysfunction is not associated with CLL in all patients; therefore, it is important to identify CLL patients with T cell defects. The role of B-cell lymphoma-2 (BCL-2) in CLL has been explored; however, few studies have examined its role in T cells in CLL patients. Herein, we have investigated the regulatory role of BCL-2 in T cells in the CLL tumor microenvironment. The expression of BCL-2 in T cells was evaluated using flow cytometry. The regulatory roles of BCL-2 were investigated using single-cell RNA sequencing (scRNA-seq) and verified using multi-parameter flow cytometry on CD4 and CD8 T cells. The clinical features of BCL-2 expression in T cells in CLL were also explored. We found a significant increase in BCL-2 expression in the T cells of CLL patients (n = 266). Single cell RNA sequencing (scRNA-seq) indicated that BCL-2+CD4+ T cells had the gene signature of increased regulatory T cells (Treg); BCL-2+CD8+ T cells showed the gene signature of exhausted cytotoxic T lymphocytes (CTL); and increased expression of BCL-2 was associated with T cell activation and cellular adhesion. The results from scRNA-seq were verified in peripheral T cells from 70 patients with CLL, wherein BCL-2+CD4+ T cells were enriched with Tregs and had higher expression of interleukin-10 and transforming growth factor-β than BCL-2−CD4+ T cells. BCL-2 expression in CD8+T cells was associated with exhausted cells (PD-1+Tim-3+) and weak expression of granzyme B and perforin. T cell–associated cytokine profiling revealed a negative association between BCL-2+ T cells and T cell activation. Decreased frequencies and recovery functions of BCL-2+T cells were observed in CLL patients in complete remission after treatment with venetoclax. BCL-2 expression in the T cells of CLL patients is associated with immunosuppression via promotion of Treg abundance and CTL exhaustion. The online version contains supplementary material available at 10.1186/s12943-022-01516-w.
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影响因子：
9
作者：
Kapoor I;Bodo J;Hill BT;Hsi ED;Almasan A
通讯作者：
Almasan A
影响因子：
100.3
作者：
Kallies, Axel;Zehn, Dietmar;Utzschneider, Daniel T.
通讯作者：
Utzschneider, Daniel T.
影响因子：
20.3
作者：
Hallek, Michael;Cheson, Bruce D.;Kipps, Thomas J.
通讯作者：
Kipps, Thomas J.
影响因子：
7.4
作者：
De Matteis S;Molinari C;Abbati G;Rossi T;Napolitano R;Ghetti M;Di Rorà AGL;Musuraca G;Lucchesi A;Rigolin GM;Cuneo A;Calistri D;Fattori PP;Bonafè M;Martinelli G
通讯作者：
Martinelli G
影响因子：
7.2
作者：
Hardwick JM;Soane L
通讯作者：
Soane L