Endogenous galectin-3 fine tunes Notch ligand regulation of Th1-Th2 polarization during Leishmania major infection

E SOARES-BERNARDES; MA TOSCANO; M LUCIANA; D HSU; P KAYE; FT LIU; E RILEY; MC ROQUE-BARRIERA; G RABINOVICH

Ventura, California

Congreso; 9th Gordon Conference Glycobiology; 2009

ASGlycobiology

Galectin-3, an immunoregulatory â-galactoside-binding lectin, has been shown to regulate cytokine production, thus influencing the development of adaptive immune responses. It has previously shown that galectin-3-deficient C57BL/6 mice (Lgals3–/–) develop a heightened Th1-polarized immune response. However, the role of galectin-3 in the Th1/Th2 differentiation is not fully understood. Here we demonstrate that susceptibility and development of Th2 immune response are affected in Lgals3–/– BALB/c mice infected with Leishmania major. Compared with wild-type (Lgals3+/+) mice, L. major-infected Lgals–/– mice showed an enhanced footpad swelling and higher parasite burden. Interestingly, at the beginning of the infection (15 days) lymph node cells from L. major-infected Lgals3–/– mice showed a skewed Th1phenotype, as demonstrated by the higher levels of proinflammatory cytokines and IFN-g.  However, at a late phase (30 days), L. major-infected Lgals3–/– mice developed a Th2-polarized immune response characterized by lower levels of IL-4, GATA-3 mRNA and, higher number of CD4+CD25+Foxp3+ cells.  Interestingly, we found a decrease of CD11c+ Jagged-1+ cells but an increase of CD11c+ Delta-4+ cells in the lymph nodes of L. major-infected Lgals3–/– mice. Using bone-marrow-derived dendritic cells, we demonstrated that, even in the absence of stimulation, Lgals3–/– dendritic cells displayed reduced mRNA levels of Jagged-1 and higher mRNA levels of Delta-4, which is compatible with their higher capacity to induce a heightened Th1 immune response. Therefore, the Th1-promoting ability of Lgals3–/– dendritic cells may be due to their higher expression of Delta-4 whereas a defect in the Th2 differentiation is related to the lower expression of Jagged-1. In conclusion, galectin-3 may interfere with the expression of Notch ligands in dendritic cells, thus determining the outcome of Th cell differentiation either in Th1 or Th2.