Galectin-9 (gal-9) is a multifunctional β-galactoside-binding lectin which is frequently released in the extra-cellular medium where it can modulate various biological activities (cell adhesion, migration), but it acts mainly as a negative regulator of the immune response. Our team has shown an intense and inappropriate production of gal-9 by malignant epithelial cells in Epstein-Barr virus-associated nasopharyngeal carcinoma. Other groups and ourselves have shown that gal-9 is very abundant in plasma samples from patients chronically infected by hepatitis C or B virus, and particularly in those with hepatocellular carcinomas. The most prominent immunosuppressive effects reported for gal-9 are the induction of apoptosis of CD4+ T-helper 1 (Th1) cells, exhaustion of CD8+ T cells, and stimulation of regulatory T cell activity. However, a recent study (and our own data) demonstrates that gal-9 can also activate and expand a subset of IFNγ; producing Th1 cells and central memory T cells in the surviving population.
Despite its critical role in regulating the immune response, our knowledge of the signaling events triggered by exogenous gal-9 in T cells remains limited. Our studies reveal that several proximal components of the TCR-CD3 complex including the Lck kinase were required for the calcium (Ca2+) mobilization induced by gal-9 in Jurkat cells. In contrast, these components were not necessary for the apoptosis pathway triggered by gal-9. These data were confirmed in human CD4+ blood T cells: Lck inhibition with a specific inhibitor abrogates Ca2+ mobilization, but not apoptosis induction in CD4+ T cells. Moreover, this cytosolic Ca2+ release leads to the production of Th1 type cytokines, i.e. IL-2 and IFNγ; also dependent on Lck. These findings support the notion that gal-9 acts on T cells by two distinct pathways: one mimicking antigen-specific activation of the TCR with a mandatory contribution of proximal elements of the TCR complex, especially Lck, and another resulting in apoptosis which is independent of this complex. More recent data suggest that the CD45 molecule could be a putative receptor for gal-9 on human T cells. Indeed, the J45.01 cell line (CD45-deficient) was not susceptible to gal-9-induced apoptosis.
In parallel to this work, we investigated the same cellular events (apoptosis and Ca2+ mobilization) in human B cells. In fact, there are currently very few publications dealing with the effects of gal-9 on B cells. Our preliminary results show that some Burkitt's lymphoma cell lines (BL2, BL41 and Ramos) and CD20+ B cells from blood, were both sensitive to gal-9-induced apoptosis. Besides, gal-9 induced a cytosolic Ca2+ mobilization in BL2 and BL41 cells which is efficiently abrogated by the chemical Lck inhibitor. In contrast, we didn't observe any Ca2+ release in the Ramos cell line, in which the Lck kinase is not functional, as well as in non-lymphoid cells. These preliminary results suggest that gal-9 activates in B cells a signaling pathway somehow similar to the TCR pathway and previously unexplored in B cells.
Citation Format: Claire Lhuillier, Clement Barjon, Toshiro Niki, Aurore Gelin, Nadira Delhem, Mitsuomi Hirashima, Ming Wei, Olivier Dellis, Pierre Busson. Exploration of the signaling pathways triggered by exogenous galectin-9 in human T and B cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B177.
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