Suppression of age-related salivary gland autoimmunity by glycosylation-dependent galectin-1-driven immune inhibitory circuits

VERÓNICA C. MARTÍNEZ ALLO; VANESA HAUK; NICOLAS SARBIA; NICOLAS A. PINTO; DIEGO CROCI; TOMAS DALOTTO MORENO; ROSA M. MORALES; SABRINA G. GATTO; MONTANA N. MANSELLE COCCO; JUAN C. STUPIRSKI,; ANGEL DELADOEY; ESTEBAN MARONNA; PRISCILA MARCAIDA; VIRGINIA DURIGAN; ANASTASIA SECCO; MARTA MAMANI; ALICIA DOS SANTOS; ANTONIO CATALAN PELLET; CLAUDIA PEREZ LEIROS; GABRIEL A. RABINOVICH*; MARTA TOSCANO* (GAR Y MR COMPARTEN ÚLTIMA AUTORÍA)

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2020

0027-8424

Aging elicits quantitative and qualitative changes in different immune components, leading to disruption of tolerogenic circuits and development of autoimmune disorders. Galectin-1 (Gal1), an endogenous glycan-binding protein, has emerged as a regulator of immune cell homeostasis by shaping the fate of myeloid and lymphoid cells. Here, we demonstrate that aged Gal1 null-mutant (Lgals1-/-) mice develop a spontaneous inflammatory process in salivary glands that resembles Sjögren´s syndrome. This spontaneous autoimmune phenotype was recapitulated in mice lacking β1,6N-acetylglucosaminyltransferase V (Mgat5), an enzyme responsible of generating 1,6-branched complex N-glycans, which serve as a major ligand for this lectin. Lack of Gal1 or its specific N-glycosylated ligands resulted in CD11c+ dendritic cells (DCs) with higher immunogenic potential, lower frequency of Foxp3+ regulatory T cells (Tregs) and increased number of CD8+ T cells with greater effector capacity. Supporting its tolerogenic activity, Gal1 expression decreased with age in autoimmunity-prone NOD mice. Treatment with recombinant Gal1 restored tolerogenic mechanisms and reduced salivary gland inflammation. Accordingly, labial biopsies from primary Sjögren´s syndrome patients showed reduced Gal1 expression concomitant with higher number of infiltrating CD8+ T cells. Thus, endogenous Gal1 serves as a homeostatic rheostat that safeguards immune tolerance and prevents age-dependent development of spontaneous autoimmunity.