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

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

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

NATL ACAD SCIENCES

Año: 2020 vol. 117 p. 6630 - 6639

0027-8424

Aging elicits quantitative and qualitative changes in differentimmune components, leading to disruption of tolerogenic circuitsand development of autoimmune disorders. Galectin-1 (Gal1), anendogenous glycan-binding protein, has emerged as a regulator ofimmune cell homeostasis by shaping the fate of myeloid andlymphoid cells. Here, we demonstrate that aged Gal1-null mutant(Lgals1−/−) mice develop a spontaneous inflammatory process insalivary glands that resembles Sjögren?s syndrome. This spontaneousautoimmune phenotype was recapitulated in mice lackingβ1,6N-acetylglucosaminyltransferase V (Mgat5), an enzyme responsiblefor generating β1,6-branched complex N-glycans, whichserve as a major ligand for this lectin. Lack of Gal1 resulted inCD11c+ dendritic cells (DCs) with higher immunogenic potential,lower frequency of Foxp3+ regulatory T cells (Tregs), and increasednumber of CD8+ T cells with greater effector capacity. Supportingits tolerogenic activity, Gal1 expression decreased with age inautoimmunity-prone nonobese diabetic (NOD) mice. Treatmentwith recombinant Gal1 restored tolerogenic mechanisms and reducedsalivary gland inflammation. Accordingly, labial biopsiesfrom primary Sjögren?s syndrome patients showed reduced Gal1expression concomitant with higher number of infiltrating CD8+T cells. Thus, endogenous Gal1 serves as a homeostatic rheostatthat safeguards immune tolerance and prevents age-dependentdevelopment of spontaneous autoimmunity.