DISSECTING THE ROLE OF PROTEIN-GLYCAN INTERACTIONS IN NEGATIVE REGULATION

MARTA A. TOSCANO; GERMAN A. BIANCO; JUAN M. ILARREGUI; LEONARDO CAMPAGNA; DIEGO O. CROCI; NORBERTO W. ZWIRNER; JORGE CORREALE; GABRIEL A. RABINOVICH

Munich

Congreso; 7th World Congress on TRAUMA, SHOCK, INFLAMMATION AND SEPTIS TSIS 2007; 2007

The International Association of Inflammation Societies

Galectin-1, a carbohydrate-binding protein found at sites of T-cell activation, has immunosuppressive effects in vivo. Administration of recombinant galectin-1 or its genetic delivery in experimental models of chronic inflammation and autoimmunity results in selective elimination of antigen-activated T cells and a T-helper (TH) 1 to TH2 shift associated with remission of inflammatory disease. In addition, selective blockade of the inhibitory effects of galectin-1 within the tumor microenvironment results in heightened T-cell-mediated tumor rejection and increased survival of TH1 effector cells. The aim of the present study is to dissect the mechanisms involved in the galectin-1-mediated regulation of Th1 and Th2 responses. We demonstrate here that TH1- and TH2-promoting stimuli can differentially regulate the glycosylation pattern of human and murine T-helper cells and modulate their susceptibility to galectin-1. While TH1- differentiated cells express the repertoire of cell surface glycans that are critical for galectin-1 binding and cell death, TH2 cells are protected from galectin-1 through differential sialylation of N- and O-glycans on cell surface glycoproteins. Consistently, galectin-1-deficient mice develop hyper-TH1 responses following specific antigenic challenge in vivo, characterized by significantly higher levels of interferon-g-producing cells (P<0.05, Student:s t test)and enhanced T-bet expression compared to wildtype mice. To evaluate the pathophysiological relevance of our findings, we examined the effects of gal-1 deletion on the development and progression of experimental autoimmune encephalomyelitis (EAE), a prototypic Th1-mediated central nervous system (CNS)disease that is used as an animal model of human multiple sclerosis. Gal-1-deficient mice developed EAE with increased severity compared to wild-type mice (P<0.05 Man Whittney test). Worsening of the disease was accompanied by a heightened autoimmune response, more diffuse CNS inflammatory infiltrates, decreased levels of CD4+ T-cell apoptosis and a profound skewing toward Th1 responses in vivo. Our findings identify a novel mechanism, based on differential glycosylation of TH1 and TH2 cell subsets, by which galectin-1 may preferentially eliminate antigenspecific TH1-effector cells with critical implications for immunotherapy.