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. 2023 Apr;37(4):e22865.
doi: 10.1096/fj.202200884R.

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

Eduardo Valli  1 , Tomás Dalotto-Moreno  2 , Helena A Sterle  1 , Santiago P Méndez-Huergo  2 , María A Paulazo  1 , Silvia I García  3   4 , Carlos J Pirola  5 , Alicia J Klecha  1 , Gabriel A Rabinovich  2   6 , Graciela A Cremaschi  1
Affiliations

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

Eduardo Valli et al. FASEB J. 2023 Apr.

Abstract

Hypothyroidism exerts deleterious effects on immunity, but the precise role of the hypothalamic-pituitary-thyroid (HPT) axis in immunoregulatory and tolerogenic programs is barely understood. Here, we investigated the mechanisms underlying hypothyroid-related immunosuppression by examining the regulatory role of components of the HPT axis. We first analyzed lymphocyte activity in mice overexpressing the 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-inflammatory cytokines 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-cell subpopulations in lymphoid tissues of hypothyroid and control mice. No differences were observed 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-Trh mice. 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 recombinant Gal-1. Finally, increased expression of Gal-1 was 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-expressing Tregs underlies immunosuppression associated with hypothyroid conditions, with critical implications in immunopathology, metabolic disorders, and cancer.

Keywords: T regulatory cells; galectin-1; hypothyroidism; thyrotropin; thyrotropin-releasing hormone.

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References

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