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Cell-autonomous iodothyronine deiodinase expression mediates seasonal plasticity in immune function.

ABSTRACT: Annual rhythms in morbidity and mortality are well-documented, and host defense mechanisms undergo marked seasonal phenotypic change. Siberian hamsters (Phodopus sungorus) exhibit striking immunological plasticity following adaptation to short winter day lengths (SD), including increases in blood leukocytes and in the magnitude of T cell-mediated immune responses. Thyroid hormone (TH) signaling is rate-limited by tissue-level expression of iodothyronine deiodinase types II and III (dio2, dio3), and dio2/dio3 expression in the central nervous system gate TH-dependent transduction of photoperiod information into the neuroendocrine system. THs are also potent immunomodulators, but their role in seasonal immunobiology remains unexamined. Here we report that photoperiod-driven changes in triiodothyronine (T3) signaling mediate seasonal changes in multiple aspects of immune function. Transfer from long days (LD) to SD inhibited leukocyte dio3 expression, which increased cellular T4?T3 catabolism. T3 was preferentially localized in the lymphocyte cytoplasm, consistent with a non-nuclear role of T3 in lymphoid cell differentiation and maturation. Exposure to SD upregulated leukocyte DNA methyltransferase expression and markedly increased DNA methylation in the dio3 proximal promoter region. Lastly, to bypass low endogenous T3 biosynthesis in LD lymphocytes, LD hamsters were treated with T3, which enhanced T cell-dependent delayed-type hypersensitivity inflammatory responses and blood leukocyte concentrations in a dose-dependent manner, mimicking effects of SD on these immunophenotypes. T3 signaling represents a novel mechanism by which environmental day length cues impact the immune system: changes in day length alter lymphoid cell T3-signaling via epigenetic transcriptional control of dio3 expression.

SUBMITTER: Stevenson TJ

PROVIDER: S-EPMC3974869 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Cell-autonomous iodothyronine deiodinase expression mediates seasonal plasticity in immune function.

Stevenson Tyler J TJ Onishi Kenneth G KG Bradley Sean P SP Prendergast Brian J BJ

Brain, behavior, and immunity 20131019

Annual rhythms in morbidity and mortality are well-documented, and host defense mechanisms undergo marked seasonal phenotypic change. Siberian hamsters (Phodopus sungorus) exhibit striking immunological plasticity following adaptation to short winter day lengths (SD), including increases in blood leukocytes and in the magnitude of T cell-mediated immune responses. Thyroid hormone (TH) signaling is rate-limited by tissue-level expression of iodothyronine deiodinase types II and III (dio2, dio3), ...[more]

PMID: 24145050

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Project description:PurposeThe development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non-small-cell lung cancer (NSCLC) who had a functional thyroid.Materials and methodsThyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases.ResultsUpon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels.ConclusionAn off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.

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Cell-autonomous iodothyronine deiodinase expression mediates seasonal plasticity in immune function.

Publications

Cell-autonomous iodothyronine deiodinase expression mediates seasonal plasticity in immune function.

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