T-helper cell regulation of CD45 phosphatase activity by galectin-1 and CD43 governs chronic lymphocytic leukaemia proliferation.
T-helper cell regulation of CD45 phosphatase activity by galectin-1 and CD43 governs chronic lymphocytic leukaemia proliferation.
复制标题
DOI：
10.1111/bjh.18285
复制
发表时间：
2022-08
影响因子：
6.5
通讯作者：
Nakken, Britt
中科院分区：
文献类型：
--
作者：
Imbery, John F.;Heinzelbecker, Julia;Jebsen, Jenny K.;McGowan, Marc;Myklebust, Camilla;Bottini, Nunzio;Stanford, Stephanie M.;Skanland, Sigrid S.;Tveita, Anders;Tjonnfjord, Geir E.;Munthe, Ludvig A.;Szodoray, Peter;Nakken, Britt
慢性淋巴细胞性白血病(CLL)以恶性成熟样B细胞为特征。支持CLL细胞存活的是慢性B细胞受体(BCR)信号；然而，新的证据表明，CLL细胞以CD40L依赖的方式响应T辅助(Th)细胞的反应而增殖。我们发现Th刺激是通过CD40L上调非恶性B细胞中CD45磷酸酶活性和BCR信号。因此，我们推测Th细胞上调CLL细胞CD45活性可能是CLL BCR信号和增殖的重要调节因子。在激活的自体Th细胞的培养系统中使用患者来源的CLL细胞，结果显示Th和CLL细胞CD45活性都增加，这与增强下游抗原受体信号和增殖有关。伴随而来的是CD45配体Galectin-1和CLL免疫表型标记CD43的表面表达增加。Galectin-1/CD43双表达定义了CD45活性增强的增殖性CLL细胞群。以Galectin-1或CD43为靶点，使用沉默、药理学或单抗策略，可抑制CD45活性和CLL细胞增殖。这些结果强调了一种机制，即激活的Th细胞通过Galectin-1和CD43介导的CD45活性调节来驱动CLL细胞BCR信号和增殖，确认CD45磷酸酶活性的调节是CLL潜在的治疗靶点。
Chronic lymphocytic leukaemia (CLL) is characterised by malignant mature‐like B cells. Supportive to CLL cell survival is chronic B‐cell receptor (BCR) signalling; however, emerging evidence demonstrates CLL cells proliferate in response to T‐helper (Th) cells in a CD40L‐dependent manner. We showed provision of Th stimulation via CD40L upregulated CD45 phosphatase activity and BCR signalling in non‐malignant B cells. Consequently, we hypothesised Th cell upregulation of CLL cell CD45 activity may be an important regulator of CLL BCR signalling and proliferation. Using patient‐derived CLL cells in a culture system with activated autologous Th cells, results revealed increases in both Th and CLL cell CD45 activity, which correlated with enhanced downstream antigen receptor signalling and proliferation. Concomitantly increased was the surface expression of Galectin‐1, a CD45 ligand, and CD43, a CLL immunophenotypic marker. Galectin‐1/CD43 double expression defined a proliferative CLL cell population with enhanced CD45 activity. Targeting either Galectin‐1 or CD43 using silencing, pharmacology, or monoclonal antibody strategies dampened CD45 activity and CLL cell proliferation. These results highlight a mechanism where activated Th cells drive CLL cell BCR signalling and proliferation via Galectin‐1 and CD43‐mediated regulation of CD45 activity, identifying modulation of CD45 phosphatase activity as a potential therapeutic target in CLL.
登录
查看更多内容
影响因子：
7.3
作者：
Dings, Ruud P. M.;Miller, Michelle C.;Nesmelova, Irina;Astorgues-Xerri, Lucile;Kumar, Nigam;Serova, Maria;Chen, Xuimei;Raymond, Eric;Hoye, Thomas R.;Mayo, Kevin H.
通讯作者：
Mayo, Kevin H.
影响因子：
16.6
作者：
Giovannone N;Liang J;Antonopoulos A;Geddes Sweeney J;King SL;Pochebit SM;Bhattacharyya N;Lee GS;Dell A;Widlund HR;Haslam SM;Dimitroff CJ
通讯作者：
Dimitroff CJ
影响因子：
11.2
作者：
Bartels, Lina;de Jong, Greta;Wagner, Koen
通讯作者：
Wagner, Koen
影响因子：
5.7
作者：
Calissano, Carlo;Damle, Rajendra N.;Chiorazzi, Nicholas
通讯作者：
Chiorazzi, Nicholas
影响因子：
2.8
作者：
Deak, Magdolna;Hornung, Akos;Kovacs, Laszlo
通讯作者：
Kovacs, Laszlo