Galectins flip the CD40 survival-and-proliferation switch off and on in autoimmunity. (101.39)

Abstract

Abstract CD40 is intimately associated with autoimmune disease. CD4+CD40+ T cells (Th40) are necessary and sufficient in transferring autoimmunity and CD40 engagement induces survival and proliferation of those cells. Several CD40 receptor constellations exist being composed of different glycoforms of CD40 and some are hybrid receptors with TNFR1 and 2. Autoimmune and non-autoimmune mouse Th40 cells differ in their CD40 glycosylation status. Here we reveal that in-vivo CD40 signals to non-autoimmune BALB/c mice access glycosylation processes and induce a reduction in glycan branching to levels seen in autoimmune strains. Such levels are known to activate T cells. CD40 signals induce a less glycosylated form of CD40 itself. We reveal an interaction of galectins 3 and 9 with CD40 in Th40 cells that differs between autoimmune and non-autoimmune conditions. Those galectins counteract each other in controlling CD40 receptor signals. Galectin-3 interaction is associated with CD40 signals leading to survival/proliferation of autoimmune NOD Th40 cells. However, the addition of galectin 9 counteracts that interaction to promote CD40 interaction with galectin-9 which thwarts the survival and proliferation signals. Therefore we suggest that CD40’s impact on glycosylation events may have far reaching consequences for immune effector molecules beyond CD40 itself and that galectins 3 and 9 are controlling a “switch” that determines whether CD40 signals lead to survival and proliferation.