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 A.; GARCÍA, SILVIA I.; PIROLA, CARLOS J.; KLECHA, ALICIA J.; RABINOVICH, GABRIEL A.; CREMASCHI, GRACIELA A.

FASEB JOURNAL

FEDERATION AMER SOC EXP BIOL

Año: 2023 vol. 37 p. 1 - 16

0892-6638

Hypothyroidism exerts deleterious effects on immunity, but the precise role ofthehypothalamic– pituitary– thyroid (HPT) axis in immunoregulatory and tolerogenicprograms is barely understood. Here, we investigated the mechanisms underly-ing hypothyroid- related immunosuppression by examining the regulatory role ofcomponents ofthe HPT axis. We first analyzed lymphocyte activity in mice over-expressing the TRH gene (Tg- Trh). T cells from Tg- Trhshowed increased prolifera-tion than wild- type (WT) euthyroid mice in response to polyclonal activation. Therelease ofTh1 pro- inflammatory cytokines was also increased in Tg- Trhand TSHlevels correlated with T-cell proliferation. To gain further mechanistic insightsinto hypothyroidism- related immunosuppression, we evaluated T-cell subpopula-tions in lymphoid tissues ofhypothyroid and control mice. No differences wereobserved in CD3/CD19 or CD4/CD8 ratios between these strains. However, thefrequency ofregulatory T cells (Tregs) was significantly increased in hypothyroid mice, and not in Tg- Trhmice. Accordingly, in vitro Tregs differentiation was morepronounced in naïve T cells isolated from hypothyroid mice. Since Tregs overex-press galectin- 1 (Gal- 1) and mice lacking this lectin (Lgals1−/−) show reduced Tregfunction, we investigated the involvement ofthis immunoregulatory lectin in thecontrol ofTregs in settings ofhypothyroidism. Increased T lymphocyte reactivityand reduced frequency ofTregs were found in hypothyroid Lgals1−/−mice whencompared to hypothyroid WT animals. This effect was rescued by the addition ofrecombinant Gal- 1. Finally, increased expression ofGal- 1 was found in Tregs puri-fied from hypothyroid WT mice compared with their euthyroid counterpart. Thus,a substantial increase in the frequency and activity ofGal- 1-expressing Tregs un-derlies immunosuppression associated with hypothyroid conditions, with criticalimplications in immunopathology, metabolic disorders, and cancer.