Dissecting thyroid hormone transport and metabolism in dendritic cells

Abstract

We reported thyroid hormone (TH) receptor expression in murine dendritic cells (DCs) and 3,5,3'-triiodothyronine (T)-dependent stimulation of DC maturation and ability to develop a Th1-type adaptive response. Moreover, an increased DC capacity to promote antigen-specific cytotoxic T-cell activity, exploited in a DC-based antitumor vaccination protocol, was revealed. However, putative effects of the main circulating TH, l-thyroxine (T) and the mechanisms of TH transport and metabolism at DC level, crucial events for TH action at target cell level, were not known. Herein, we show that T did not reproduce those registered T-dependent effects, finding that may reflect a homoeostatic control to prevent unspecific systemic activation of DCs. Besides, DCs express MCT10 and LAT2 TH transporters, and these cells mainly transport T with a favored involvement of MCT10 as its inhibition almost prevented T saturable uptake mechanism and reduced T-induced IL-12 production. In turn, DCs express iodothyronine deiodonases type 2 and 3 (D2, D3) and exhibit both enzymatic activities with a prevalence towards TH inactivation. Moreover, T increased MCT10 and LAT2 expression and T efflux from DCs but not T uptake, whereas it induced a robust induction of D3 with a parallel slight reduction in D2. These findings disclose pivotal events involved in the mechanism of action of THs on DCs, providing valuable tools for manipulating the immunogenic potential of these cells. Furthermore, they broaden the knowledge of the TH mechanism of action at the immune system network.

Thyroid Hormone Action on Innate Immunity

“…In this regard, DCs express MCT10 and LAT2 TH transporters, and mainly transport T3 with a favored involvement of MCT10, as its inhibition almost prevented T3 saturable uptake mechanism and reduced T3-induced IL-12 production. In addition, DCs express D2 and D3, and exhibit both enzymatic activities with a prevalence toward TH inactivation (97).…”

Dendritic Cells Exposed to Triiodothyronine Deliver Pro-Inflammatory Signals and Amplify IL-17-Driven Immune Responses

“…Thyroid hormones play key roles linking immune and endocrine networks. Our laboratory has centered the attention in elucidating the role of T3 in the initiation and termination of adaptive immune responses with a special focus on its role within the DC compartment [9][10][11][12]14]. Although an initial therapeutic impact of T3-conditioned DCs was revealed in vivo in cancer settings [12,13], the precise characterization of the immune landscape modulated by these cells is still lacking.…”

“…Moreover, we identified a major role of T3 in induction of cytotoxic T cells and protection against tumor development via DC activation [12,13]. Recently, we reported the scarce effect of the main circulating TH, thyroxine (T4) on DC functionality, and described the mechanisms of TH transport across DC surface as well as TH metabolism in these cells [14].…”

Thyroid Hormone Transporters

“…To what extent both transporters also cofacilitate renal thyroid hormone uptake and/or efflux has not been addressed so far. Of note, MCT10 and LAT2 are also coexpressed in cells related to the immune system, such as microglial cells and dendritic cells (449). Moreover, in dendritic cells, T3 was shown to induce interleukin-12 secretion and this response was blunted on pharmacological blocking of MCT10, suggesting that Mct10 mediates T3 transport in this cell type (449).…”