Hypothyroidism-associated immunosuppression involves induction of galectin-1- producing regulatory T cells

VALLI, EDUARDO; DALOTTO-MORENO, TOMÁS; STERLE, HELENA A.; MÉNDEZ-HUERGO, SANTIAGO P.; PAULAZO, MARÍA ALEJANDRA; GARCÍA, SILVIA I.; PIROLA, CARLOS J.; KLECHA, ALICIA J.; RABINOVICH, GABRIEL A.; CREMASCHI, GRACIELA A.

FASEB JOURNAL

FEDERATION AMER SOC EXP BIOL

Lugar: Bethesda; Año: 2023 vol. 37

0892-6638

Hypothyroidism exerts deleterious effects on immunity, but the precise role of the hypothalamic-pituitary-thyroid (HPT) axis in immunoregulatory and tolerogenic programs is barelyunderstood. Here we investigated the mechanisms underlying hypothyroid-relatedimmunosuppression by examining the effects of components of the HPT axis. We first analyzedlymphocyte activity in mice overexpressing the TRH gene (Tg-Trh). T cells from Tg-Trhproliferated faster than wild type (WT) euthyroid mice in response to polyclonal activation. Therelease of Th1 proinflammatory cytokines was also increased in Tg-Trh, and TSH levelscorrelated with cell proliferation. To gain further insight into hypothyroidism-relatedimmunosuppression, we evaluated T subpopulations in lymphoid tissues of hypothyroid andcontrol mice. No differences were observed in CD3/CD19 or CD4/CD8 ratios. The frequency ofregulatory T cells (Tregs) was significantly increased in hypothyroid mice, and not in Tg-Trhmice. Accordingly, in vitro Tregs differentiation was more pronounced in naïve T cells isolatedfrom hypothyroid mice. Tregs overexpress galectin-1 (Gal-1), an immunoregulatory lectin, andmice lacking this lectin (Lgals1 -/- ) show reduced Treg function. We investigated its involvementin the control of Tregs in hypothyroidism. Increased T lymphocyte reactivity and reducedfrequency of Tregs were found in hypothyroid Lgals1-/- mice when compared to the hypothyroidgroup of WT animals. Finally, increased expression of Gal-1 was found in Tregs purified fromhypothyroid WT mice compared with their euthyroid counterpart. Thus, a substantial increase inthe frequency and activity of galectin-1-expressing Tregs underlies immunosuppressionassociated with hypothyroid conditions, with critical implications in immunopathology,metabolic disorders and cancer.