Research - Institute of Genetics - Microbial and Plant Genetics Unit - Laboratory of Lymphocyte and Signal Transduction

Éva MONOSTORI
scientific advisor, principal investigator

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Ágnes CZIBULA research associate
Roberta FAJKA-BOJA research associate
Éva KRISTON-PÁL junior research associate
Ákos HORNUNG Ph.D. student
Julianna NOVÁK Ph.D. student
Enikő SZABÓ Ph.D. student
Andrásné GERCSÓ technician

LYMPHOCYTE SIGNAL TRANSDUCTION LABORATORY

Many factors participate in the regulation of peripheral immune tolerance and maintenance of the immune homeostasis by controlling the inflammatory and autoimmune processes in mammals. A powerful mechanism is the modulation of the pattern of cell surface glycosylation and the expression of soluble or cell-bound lectins interacting with their ligands. Among these lectins, galectin-1 is one of the master immunoregulators.


Control of T cell viability by extracellular galectin-1

Although galectin-1 is widely expressed in a large number of tissues and fulfills pleiotropic extracellular functions, it specifically acts on the immune response by preventing autoimmune and inflammatory processes. Its inhibitory effects derive from reducing the production of inflammatory cytokines and inducing apoptosis of activated T lymphocytes. These functions encourage us to think about galectin-1 as a potential therapeutic drug in autoimmune and inflammatory diseases. On the other hand, galectin-1 contributes to tumor progression, partly by participating in generation of tumor immunoprivilege. The molecular mechanism of T cell apoptosis induced by galectin-1 has been recently described in our laboratory (Fig. 1). The apoptotic pathway involves the obligatory activation of tyrosine kinases, p56lck and ZAP 70 followed by tyrosine phosphorylation of intracellular substrates. After this, acid sphingomyelinase converts sphingomyelin into apoptotic second messenger, ceramide and as a consequence, depolarization of the mitochondrial membrane occurs. Final steps include the activation of caspase 9 and caspase 3 resulting in massive proteolysis of proteins and breakdown of nuclear DNA. In these studies apoptosis has been induced by recombinant galectin-1; however, we have proved that cell-derived galectin-1 reduces T-cell viability via an identical pathway (Fig. 2). Galectin-1 secreted by the tumor cells does not appear as a soluble factor, rather it couples to its glycoconjugate ligands on the tumor cell surface. Hence T-cell apoptosis induced by the tumor cells in co-culture system requires direct cell-cell interaction.



Figure 1. Galectin-1 induced apoptotic pathway. Inhibition of p56lck and ZAP 70 tyrosine kinases, activity of acid sphingomyelinase and release of ceramide, the decrease of the mitochondrial membrane potential or activation of caspases result in failure of T-cell apoptosis induced by recombinant, soluble galectin-1.



Figure 2. Tumor cell-derived galectin-1 induces T-cell apoptosis on identical pathway as recombinant soluble galectin-1. HeLa: galectin-1 non-producing tumor cells, U87: galectin-1 producing tumor cells.

Selected publications

Monostori, E., Desai, D., Brown, M.H., Cantrell, D.A. and Crumpton, M.J. (1991). Activation of human T lymphocytes via CD2antigen results in tyrosine phosphorylation of T cell antigen receptors -chains. J. Immunol. 144: 1010.

Fajka-Boja, R., Szemes, M., Ion, G., Légrádi, Á., Caron, M. and Monostori, É. (2002). Receptor tyrosine phosphatase, CD45 binds Galectin-1 but does not mediate its apoptotic signal in T cell lines. Immunol. Lett. 82/1-2: 149-154.

Legradi, A., Chitu, V., Szukacsov, V., Fajka Boja, R., Szucs, K.S. and Monostori, E. (2004). Lysophosphatidylcholine is a regulator of tyrosine kinase activity and intracellular Ca2+ level in Jurkat T cell line. Immunol. Lett. 91: 17-21.

Vas, V., Fajka-Boja, R., Ion, G., Dudics, V., Monostori, É. and Uher, F. (2005). Biphasic effect of recombinant galectin-1 on the growth and death of early hematopoietic cells. Stem Cells 23: 279-287.

Ion, G., Fajka-Boja, R., Tóth, G.K., Caron, M. and Monostori, É. (2005). Role of p56 lck and ZAP 70 mediated tyrosine phosphorylation in galectin-1 induced cell death. Cell Death Differ. 12(8): 1145-1147.

Ion, G., Fajka-Boja, R., Kovács, F., Szebeni, G., Gombos, I., Czibula, Á., Matkó, J. and Monostori, É. (2006). Acid sphingomyelinase mediated release of ceramide is essential to trigger the mitochondrial pathway of apoptosis by galectin-1. Cell Signal. 18: 1887-1896.

Kiss, J., Kunstár, A., Fajka-Boja, R., Dudics, V., Tóvári, F., Légrádi, Á., Monostori, É. and Uher, F. (2007). A novel anti-inflammatory function of human galectin-1: inhibition of hematopoietic progenitor cell mobilization. Exp. Hematol. 35: 305-313.

Urbán, V.S., Kiss, J., Kovács, J., Gócza, E., Vas, V., Monostori, É. and Uher, F. (2008). Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells 26: 244-253.

Fajka-Boja, R., Blaskó, A., Kovács-Sólyom, F., Szebeni, G.J., Tóth, G.K. and Monostori, É. (2008). Co-localization of galectin-1 with GM1 ganglioside in the course of its clathrin- and raft-dependent endocytosis. Cell. Mol. Life Sci. 65(16): 2586-2593.

Kovács-Sólyom, F., Blaskó, A., Fajka-Boja, R., Katona, RL., Végh, L., Novák, J., Szebeni, GJ., Krenács, L., Uher, F., Tubak, V., Kiss, R., Monostori, É. (2010). Mechanism of tumor cell-induced t-cell apoptosis mediated by galectin-1. Immunol. Lett., 127: 108–118.

Wéber,E., Hetényi, A., Váczi, B., Szolnoki, É., Fajka-Boja, R., Tubak, V., Monostori, É., Martinek, T. A. (2010). Galectin-1–Asialofetuin interaction is inhibited by peptides containing the tyr-xxx-tyr motif acting on the glycoprotein. Chembiochem, 11: 228-34.

Hegyi, B., Sági, B., Kovács, J., Kiss, J., Urbán, VS., Mészáros, G., Monostori, É Uher, F. (2010). Identical, similar or different? Learning about immunomodulatory function of mesenchymal stem/multipotent stromal cells isolated from various mouse tissues: bone marrow, spleen, thymus, and aorta wall. Int. Immunol. In Press

B Hegyi, B Sági, J Kovács, J Kiss, VS Urbán, G Mészáros, É Monostori, and F Uher. Identical, Similar or Different? Learning about Immunomodulatory Function of Mesenchymal Stem/Multipotent Stromal Cells Isolated from Various Mouse Tissues: Bone Marrow, Spleen, Thymus, and Aorta Wall. Int Immunol 22 (2010) 551-9