Suppression of Age-Related Salivary Gland Autoimmunity by Glycosylation-Dependent galectin-1-driven Immune Inhibitory Circuits

VERÓNICA C MARTÍNEZ ALLO ; VANESA HAUK ; NICOLAS SARBIA ; NICOLÁS A PINTO; DIEGO O CROCI ; TOMÁS DALOTTO-MORENO ; ROSA M MORALES ; SABRINA G GATTO ; MONTANA N MANSELLE COCCO ; JUAN C STUPIRSKI ; ÁNGEL DELADOEY; ESTEBAN MARONNA ; PRISCILA MARCAIDA ; ANASTASIA SECCO ; CLAUDIA PÉREZ LEIROS; GABRIEL A RABINOVICH; MARTA A TOSCANO

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 for generating β1,6-branched complex N-glycans, which serve as a major ligand for this lectin. Lack of Gal1 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 nonobese diabetic (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.