☆ 4.5 Article

GM1 controlled lateral segregation of tyrosine kinase Lck predispose T-cells to cell-derived galectin-1-induced apoptosis

MOLECULAR IMMUNOLOGY (2014)

Journal

MOLECULAR IMMUNOLOGY

Volume 57, Issue 2, Pages 302-309

Publisher

PERGAMON-ELSEVIER SCIENCE LTD

DOI: 10.1016/j.molimm.2013.10.010

Keywords

Galectin-1; Lck; CD45; GM1; Apoptosis

Funding

Hungarian Scientific Research Fund [OTKA PD 75938, OTKA K 69047, NKTH-OTKA CK 78188, TAMOP-4.2.2.A-11/1/KONV-2012-0035]
Janos Bolyai Research Fellowship of the Hungarian Academy of Sciences

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Abstract

One prominent immunoregulatory function of galectin-1 (Gal-1), a beta-galactoside binding mammalian lectin, is induction of apoptosis in activated T-cells by a process depending on the activity of Src family tyrosine kinase, Lck. Although the requirement for Lck in Gal-1 induced T-cell death and the ability of Gal-1 to affect the membrane localization of extracellular Gal-1-binding proteins have been well documented, the consequence of the complex and related reorganization of extra- and intracellular signaling components upon Gal-1 treatment of T-cells has not yet been revealed. Therefore, we have analyzed the plasma membrane movement of Lck upon Gal-1 triggered signaling, and the significance of this event in Gal-1 induced T-cell death. Non-receptor tyrosine kinase, Lck primarily localized in the synapse of tumor cell-T-cell during 15 min of the established direct cell contact. Later, after 30 min, a lateral segregation of Lck from the cell synapse was observed. The migration of Lck to the opposite of the cell contact apparently depended on the expression and cell surface presentation of Gal-1 on the effector (tumor) cells and was accompanied by phosphorylation on the negative regulatory tyrosine residue, Tyr505. Receptor tyrosine phosphatase, CD45 played crucial role in this event since CD45 deficiency or inhibition of its phosphatase activity resulted in the failure of Lck membrane movement. Level of the Gal-l-binding glycolipid GM1 ganglioside also essentially regulated Lck localization. Segregation of Lck and Gal-1 induced apoptosis was diminished in T-cells with low GM1 expression compared to T-cells with high GM1. Our results show that spatial regulation of Lck by CD45 and GM1 ganglioside determines the outcome of apoptotic response to Gal-1 and this local regulation may occur only upon intimate effector (Gal-1 expressing) cell-T-cell attachment. (C) 2013 Elsevier Ltd. All rights reserved.

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T-helper cell regulation of CD45 phosphatase activity by galectin-1 and CD43 governs chronic lymphocytic leukaemia proliferation

John F. Imbery, Julia Heinzelbecker, Jenny K. Jebsen, Marc McGowan, Camilla Myklebust, Nunzio Bottini, Stephanie M. Stanford, Sigrid S. Skanland, Anders Tveita, Geir E. Tjonnfjord, Ludvig A. Munthe, Peter Szodoray, Britt Nakken

Summary: Chronic lymphocytic leukaemia (CLL) is a malignancy characterized by mature B cells. Emerging evidence shows that CLL cells proliferate in response to T-helper (Th) cells in a CD40L-dependent manner. The study demonstrates that Th cells upregulate CD45 activity in CLL cells, leading to enhanced downstream antigen receptor signaling and proliferation. The increased expression of Galectin-1 and CD43, both of which are involved in CD45 regulation, was also observed. Targeting Galectin-1 or CD43 could dampen CD45 activity and CLL cell proliferation. These findings suggest that modulation of CD45 phosphatase activity could be a potential therapeutic target in CLL.

BRITISH JOURNAL OF HAEMATOLOGY (2022)