Tolerogenic signals delivered from dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving IL-27 and IL-10

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

Viña del Mar, Chile.

Congreso; 9th Latin-American Congress of Immunology; 2009

Latin-American Association of Immunology

617 Tolerogenic signals delivered from dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving IL-27 and IL-10 Juan Mart¨ªn Ilarregui1, Diego Omar Croci1, Germ¨¢n Ariel Bianco1, Marta Alicia Toscano1, Mariana Salatino1, M¨®nica Vermeulen2, Jorge Geffner2, Gabriel Adrian Rabinovich1 1 Lab Inmunopatolg¨ªa, IbyME-CONICET, Argentina 2 IIHEMA, Academia Nacional de Medicina, Argentina Despite their central role in orchestrating immunity, dendritic cells (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. Both human monocyte-derived DCs matured in the presence of LPS and galectin- 1 and murine bone marrow-derived DCs differentiated in the presence of galectin-1 (DCGal1) suppressed mixed leukocyte reactions, promoted T-cell tolerance and altered the IFN-¦Ã, IL-17 and IL-10 secretion (p<0.05). A mechanistic analysis revealed that DCGal1 had increased activation of the JAK2-STAT3 pathway compared to control DCs. Moreover, DCGal1 had higher levels of the p28 and EBI3 subunits of IL-27, a cytokine that mediates the induction of IL-10-producing T (Tr1) cells (p<0.05). In in vivo settings, DCGal1 were not capable of protecting against challenge with B16 melanoma compared to control DCs and instead fostered a tolerogenic microenvironment at sites of tumor growth (p<0.05). Furthermore, treatment of MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) with DCGal1 resulted in reduced clinical severity with lower IL-17 and IFN-¦Ã and higher IL-10 production in wild-type, but not in IL-27 receptor-deficient ¦Á- or IL-10-deficient mice (p<0.05). 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