Galectin-8 Induces Apoptosis in Jurkat T Cells by Phosphatidic Acid-mediated ERK1/2 Activation Supported by Protein Kinase A Down-regulation

Abstract

Galectins have been implicated in T cell homeostasis playing complementary pro-apoptotic roles. Here we show that galectin-8 (Gal-8) is a potent pro-apoptotic agent in Jurkat T cells inducing a complex phospholipase D/phosphatidic acid signaling pathway that has not been reported for any galectin before. Gal-8 increases phosphatidic signaling, which enhances the activity of both ERK1/2 and type 4 phosphodiesterases (PDE4), with a subsequent decrease in basal protein kinase A activity. Strikingly, rolipram inhibition of PDE4 decreases ERK1/2 activity. Thus Gal-8-induced PDE4 activation releases a negative influence of cAMP/protein kinase A on ERK1/2. The resulting strong ERK1/2 activation leads to expression of the death factor Fas ligand and caspase-mediated apoptosis. Several conditions that decrease ERK1/2 activity also decrease apoptosis, such as anti-Fas ligand blocking antibodies. In addition, experiments with freshly isolated human peripheral blood mononuclear cells, previously stimulated with anti-CD3 and anti-CD28, show that Gal-8 is pro-apoptotic on activated T cells, most likely on a subpopulation of them. Anti-Gal-8 autoantibodies from patients with systemic lupus erythematosus block the apoptotic effect of Gal-8. These results implicate Gal-8 as a novel T cell suppressive factor, which can be counterbalanced by functionblocking autoantibodies in autoimmunity.

Galectin-8 binds to LFA-1, blocks its interaction with ICAM-1 and is counteracted by anti-Gal-8 autoantibodies isolated from lupus patients

“…We have previously shown that anti-Gal-8 autoantibodies produced by SLE patients block the interaction of Gal-8 with β1 integrins involved in its apoptotic action upon activated T cells (Norambuena et al, 2009). Autoantibodies against diff erent members of the galectin family such as Gal-1, -2, -3, and -4 been detected in patients with diff erent types of autoimmune diseases and in cancer (Lutomski et al, 1997;Giordanengo et al, 2001;Jensen-Jarolim et al, 2001;Lim et al, 2002;Romero et al, 2006;Montiel et al, 2010).…”

“…All these data indicate that incremented LFA-1 function promotes autoimmune disorders, whereas the contrary occurs when LFA-1 function decreases. Therefore, in addition to inducing apoptosis of activated T cells (Norambuena et al, 2009), Gal-8 might also exert an immunosuppressive action by blocking LFA-1 function. It has been reported that Gal-8 is endocytosed after binding to the cell surface (Carlsson et al, 2007), thus Gal-8 may remove LFA-1 from the cell surface and inhibit its interaction with ICAM-1.…”

“…In naïve T cells, Gal-8 at high concentration induces proliferation in the absence of antigen, while at low concentration it costimulates antigen-specifi c activation (Tribulatti et al, 2009). Once activated, T cells undergo apoptosis in response to Gal-8, involving an enhanced expression of FasL receptor (Norambuena et al, 2009). In B cells, Gal-8 promotes diff erentiation toward plasma cells (Tsai et al, 2011), while neutrophils respond to this lectin by activating their plasma membrane NADPH-oxidase (Nishi et al, 2003).…”

“…Patients with SLE, the prototypic autoimmune disease, frequently generate anti-Gal-8 autoantibodies that block adhesion and spreading of Jurkat T cells in a Gal-8 matrix . These antibodies also decrease Gal-8-induced apoptosis of Jurkat T cells (Norambuena et al, 2009). To understand the role of Gal-8 in the immune system and the pathogenic potential of anti-Gal-8 autoantibodies it is necessary to identify functionally relevant Gal-8 counter-receptors.…”

“…In the immune system Gal-8 can play important roles in the homeostasis of T- Tribulatti et al, 2007;Norambuena et al, 2009;Tribulatti et al, 2009;Tribulatti et al, 2012) and B-cells (Tsai et al, 2011). Gal-8 expression in the thymus and its pro-apoptotic eff ects on CD4 high CD8 high thymocytes suggest a role in shaping the T cell repertoire (Tribulatti et al, 2007).…”