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

EDUARDO VALLI; TOMÁS DALOTTO-MORENO; HELENA A. STERLE; SANTIAGO P. MÉNDEZ-HUERGO,; MARÍA A. PAULAZO; SILVIA I. GARCÍA; CARLOS J. PIROLA; ALICIA J. KLECHA; GABRIEL A. RABINOVICH (CO-SENIOR); GRACIELA CREMASHI (*CO-SENIORS)

FASEB JOURNAL

FEDERATION AMER SOC EXP BIOL

Lugar: Bethesda; Año: 2023

0892-6638

Hypothyroidism exerts deleterious effects on immunity, but the precise role of thehypothalamic–pituitary–thyroid (HPT) axis in immunoregulatory and tolerogenicprograms is barely understood. Here, we investigated the mechanisms underlyinghypothyroid-related immunosuppression by examining the regulatory role ofcomponents of the HPT axis. We first analyzed lymphocyte activity in mice overexpressingthe TRH gene (Tg-Trh). T cells from Tg-Trh showed increased proliferation than wild-type(WT) euthyroid mice in response to polyclonal activation. The release of Th1 pro-inflammatorycytokines was also increased in Tg-Trh and TSH levels correlated with T-cell proliferation. To gain further mechanistic insights into hypothyroidism-related immunosuppression, we evaluated T-cellsubpopulations in lymphoid tissues of hypothyroid and control mice. No differences wereobserved in CD3/CD19 or CD4/CD8 ratios between these strains. However, the frequency of regulatory 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 isolated from hypothyroid mice. Since Tregs overexpress galectin-1 (Gal-1) and mice lacking this lectin (Lgals1−/−) show reduced Treg function, we investigated the involvement of this immunoregulatory lectin in the control of Tregs in settings of hypothyroidism. Increased T lymphocyte reactivity and reduced frequency of Tregs were found in hypothyroid Lgals1−/− mice when compared to hypothyroid WT animals. This effect was rescued by the addition of Finally, increased expression of Gal-1was found in Tregs purified from hypothyroid WT mice compared with their euthyroid counterpart. Thus, a substantial increase in the frequency and activity of Gal-1- expressingTregs underlies immunosuppression associated with hypothyroid conditions, with criticalimplications in immunopathology, metabolic disorders, and cancer