Thyroid Hormone Action on Innate Immunity

Abstract

The interplay between thyroid hormone action and the immune system has been established in physiological and pathological settings. However, their connection is complex and still not completely understood. The thyroid hormones (THs), 3,3',5,5' tetraiodo-L-thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3) play essential roles in both the innate and adaptive immune responses. Despite much research having been carried out on this topic, the available data are sometimes difficult to interpret or even contradictory. Innate immune cells act as the first line of defense, mainly involving granulocytes and natural killer cells. In turn, antigen presenting cells, macrophages and dendritic cells capture, process and present antigens (self and foreign) to naïve T lymphocytes in secondary lymphoid tissues for the development of adaptive immunity. Here, we review the cellular and molecular mechanisms involved in T4 and T3 effects on innate immune cells. An overview of the state-of-the-art of TH transport across the target cell membrane, TH metabolism inside these cells, and the genomic and non-genomic mechanisms involved in the action of THs in the different innate immune cell subsets is included. The present knowledge of TH effects as well as the thyroid status on innate immunity helps to understand the complex adaptive responses achieved with profound implications in immunopathology, which include inflammation, cancer and autoimmunity, at the crossroads of the immune and endocrine systems.

Keywords: dendritic cells; innate immunity; macrophages; natural killer cells; neutrophils; thyroid hormones.

Figure 1

Effects of thyroid hormones 3,3′,5,5′ tetraiodo-L-thyroxine (T4) and 3,3′,5-triiodo-L-thyronine (T3) on innate immune cell subsets. The main reported effects of T3 and/or T4 in Neutrophils, Natural Killer (NK) cells, Macrophages and Dendritic Cells are depicted. Particular differences among the diverse origins of the cells (human, mice, cell lines, and/or tissue source) are shown and discussed in the main text.

Figure 2

3,3′,5-triiodo-L-thyronine (T3) promotes Dendritic Cell (DC) maturation and function, driving proinflammatory and cytotoxic adaptive responses. (Top) T3 promotes DC phenotypic maturation upregulating MHCII and costimulatory molecules. The functional DC activation promotes a proinflammatory cytokine phenotype (increased production of IL-12, IL-6, IL-23, IL-1β, and TGFβ1) that drives adaptive responses favoring the development of Th1 and Th17 T cells, IL-17-producing γδ T cells, and cytotoxic T cells. In contrast, the Treg population is restrained. T3-conditioned DCs also augment CCR7 expression, which favors their migration to lymph nodes, where they present processed antigens in the context of MHCII to specific T cell receptors (TCR) from naïve T cells. T3 also modulates the immune checkpoint, reducing PDL expression on DCs and triggering the down-regulation of PD-1-expressing T cells (not shown). (Bottom) DCs take up T3 more effectively than T4 through MCT10 and LAT2. Inside DCs, D2 catalyzes the conversion of T4 to T3, whereas D3 inactivates T3 resulting in T2. These cells mainly express TRβ1 with a preferred cytoplasmic localization, where it co-localizes with Akt. Upon T3 binding to TRβ1, Akt is activated and translocated to the nucleus. This mechanism includes IκB degradation and thus NF-κB cytoplasmic-nuclear shuttling that acts as a transcription factor upregulating TRβ1 expression. An intact T3-TRβ1 signaling is essential for T3-dependent DC induced effects.