Galectin-1 instructs the differentiation of regulatory dendritic cells (DCs) that promote an interleukin (IL)-27- and IL-10-mediated immunoregulatory circuit

ILARREGUI JM; CROCI DO; BIANCO GA; TOSCANO MA; SALATINO M; VERMEULEN ME; GEFFNER JR; RABINOVICH GA

Cambridge, UK

Workshop; 10th International Workshop on Carcinoma-associated Mucins.; 2009

body { background: #FFFFFF; margin: 0px; padding: 0px; } Despite their central role in orchestrating immunity, DCs may respond to inhibitory signals by becoming tolerogenic. Here, we evaluated the impact of galectin-1, an endogenous glycan-binding protein with anti-inflammatory properties, on the physiology of DCs. Bone marrow-derived mouse DCs differentiated in the presence of galectin-1 (DCGal1) suppressed mixed leukocyte reactions, promoted T-cell tolerance in vivo and modulated the IFN-γ/IL-17/IL-10 ratio. A mechanistic analysis revealed that DCGal1 had increased activation of the JAK2-STAT3 pathway compared to control DC. Moreover, DCGal1 showed higher levels of the p28 and EBI3 subunits of IL-27, a cytokine that mediates the induction of IL-10-producing T (Tr1) cells. In addition, DCGal1 were unable to protect against challenge with B16 melanoma compared to control DC and instead fostered a tolerogenic microenvironment at sites of tumor growth. Furthermore, treatment of MOG35-55-induced Experimental Autoimmune Encephalomyelitis (EAE) with DCGal1 resulted in reduced clinical severity with lower IL-17 and IFN-γ and higher IL-10 production in wild-type, but not in IL-27 receptor α- or IL-10-deficient mice. In contrast, DCs lacking galectin-1 (Lgals1-/-) had greater immunogenic potential in both in vitro and in vivo settings. Consistent with its regulatory function, galectin-1 expression was increased on DCs exposed to tolerogenic stimuli and most abundant from the peak through the resolution of autoimmune pathology. Galectin-1-sufficient DCs isolated from spleens at day 21 of EAE (peak of the disease) and adoptively transferred into Lgals1-/- mice at the day of disease onset successfully restored T-cell tolerance and contributed to the resolution of autoimmune inflammation. This effect was reflected by the reduced clinical severity, diminished IL-17 and IFN-g production and augmented IL-10 secretion by lymph node cells from Lgals1-/- mice receiving wild-type DCs, compared to Lgals1-/- mice receiving DCs devoid of this protein. Our findings identify a tolerogenic circuit linking galectin-1 signaling, IL-27-producing DCs and IL-10-secreting T cells with broad therapeutic implications in immunopathology.