Differential glycosylation of T helper cell subsets selectively regulates susceptibility to galectin-1-induced cell death

M. A. TOSCANO; G. A. BIANCO; J. M. ILARREGUI; L. CAMPAGNA; D. O. CROCI; N. W. ZWIRNER; F. POIRIER; E. M. RILEY; L. G. BAUM; G. A. RABINOVICH

Rio de Janeiro

Congreso; 13th International Congress of Immunology ImmunoRio 2007; 2007

Inatrnacional Asociation of Immunologist

Galectin-1, a carbohydrate-binding protein found at sites of T-cell activation, hasimmunosuppressive effects in vivo. Administration of galectin-1 in experimental models ofchronic inflammation and autoimmunity results in selective elimination of antigen-activated Tcells and a T-helper (Th)1 to Th2 shift associated with remission of inflammatory disease. Inaddition, selective blockade of the inhibitory effects of galectin-1 within the tumormicroenvironment results in heightened T-cell-mediated tumor rejection and increased survivalof Th1 effector cells. The aim of the present study is to dissect the mechanisms involved in thegalectin-1-mediated regulation of Th1 and Th2 responses. We demonstrate here that Th1- andTh2-promoting stimuli can differentially regulate the glycosylation pattern of human and murineT-helper cells and modulate their susceptibility to galectin-1. While Th1-differentiated cellsexpress the repertoire of cell surface glycans that are critical for galectin-1 binding and celldeath, Th2 cells are protected from galectin-1 through differential sialylation of N- and Oglycanson cell surface glycoproteins. Consistently, in vitro activation of galectin-1-deficient (gal-1-/-) CD4+ T cells results in enhanced Th1 cytokine secretion compared to wild type littermates[(IFN-��: 17±5.3 ng/ml vs. 3.2±1.3 ng/ml; P<0.05); (IL-2: 4.1±1.5 ng/ml vs. 1.9±0.2 ng/ml;P<0.05)]. Furthermore, gal-1-/- mice develop hyper-Th1 responses following specific antigenicchallenge in vivo, characterized by significantly higher levels of IFN-��-producing cells (P<0.05)and enhanced T-bet expression compared to wild-type mice. Our findings identify a novelmechanism, based on differential glycosylation of Th1 and Th2 cell subsets, by which galectin-1preferentially eliminates antigen-specific TH1-effector cells with critical implications forimmunotherapy.