Galectin-1 instructs the differentiation of regulatory dendritic cells (DC) with tolerogenic potential in cancer and autoimmunity

J. M. ILARREGUI; G. A. BIANCO; M. VERMEULEN; M. A. TOSCANO; D. O. CROCI; J. GEFFNER; G. A. RABINOVICH

Rio de Janeiro, Brazil

Congreso; 13th International Congress of Immunology; 2007

We have recently demonstrated that galectin-1 plays a role in immunoregulation and tumor-immune escape. Yet, the cellular mechanisms involved in this effect are still obscure. Here, we evaluated the impact of galectin-1 on the physiology of monocyte-derived human DC (MoDC) and bone marrow-derived murine DC (BMDC). Addition of galectin-1 to cultures of human monocytes resulted in a dose-dependent inhibition of immature DC differentiation. Moreover, MoDC maturated with LPS in the presence of galectin-1 suppressed mixed leukocyte reactions (MLRs) stimulated with control DC and modulated the IFN-ã/IL-10 ratio (p<0.01) in a dose-dependent manner. A mechanistic analysis revealed an increased activation of the STAT3 pathway, with no evidence of apoptosis or induction of FoxP3+ Tregs. However, BMDC differentiated in the presence of galectin-1 (Gal-1-BMDC) showed a regulatory phenotype reflected by their ability to suppress an antigen-specific T-cell responses in vivo (p<0.05). In addition, Gal-1-BMDC were unable to protect against challenge with B16 melanoma compared to control DC (p<0.05). Furthermore, treatment of MOG35-55-induced Experimental Autoimmune Encephalomyelitis (EAE) with Gal-1-BMDC resulted in reduced clinical and pathological severity with higher levels of IL-10 (p<0.001). Finally, investigation of BMDC from gal-1-/- mice revealed higher MHC II expression upon maturation and significantly higher capacity to stimulate MLRs (p<0.05) than wt mice. We conclude that Gal-1 plays a critical role in the generation of human and murine regulatory DC with tolerogenic potential in autoimmunity and cancer. ã/IL-10 ratio (p<0.01) in a dose-dependent manner. A mechanistic analysis revealed an increased activation of the STAT3 pathway, with no evidence of apoptosis or induction of FoxP3+ Tregs. However, BMDC differentiated in the presence of galectin-1 (Gal-1-BMDC) showed a regulatory phenotype reflected by their ability to suppress an antigen-specific T-cell responses in vivo (p<0.05). In addition, Gal-1-BMDC were unable to protect against challenge with B16 melanoma compared to control DC (p<0.05). Furthermore, treatment of MOG35-55-induced Experimental Autoimmune Encephalomyelitis (EAE) with Gal-1-BMDC resulted in reduced clinical and pathological severity with higher levels of IL-10 (p<0.001). Finally, investigation of BMDC from gal-1-/- mice revealed higher MHC II expression upon maturation and significantly higher capacity to stimulate MLRs (p<0.05) than wt mice. We conclude that Gal-1 plays a critical role in the generation of human and murine regulatory DC with tolerogenic potential in autoimmunity and cancer.