Further insights into thyroid hormone (TH) action at the initiation of adaptive immunity: Triiodothyronine (T3) tilts the balance towards a pro-inflammatory profile

ALAMINO VA; MONTESINOS, MM; GIGENA N; BLIDNER AG; MASINI-REPISO AM; RABINOVICH GA; PELLIZAS CG

Orlando

Congreso; 15th International Thyroid Congress (ITC); 2015

American Thyroid Association

Introduction: We reported TH receptor β1 expression in mice dendritic cells (DCs), the main antigen (Ag)-presenting cells, and T3-dependent stimulation of DC maturation and ability to develop a Th1-type response. Moreover, T3 reduced DC apoptosis, and increased DC ability to stimulate a cytotoxic Ag-specific response and Ag cross-presentation. In agreement, T3 stimulated DC-based immunotherapy reduced the incidence of B16 melanoma establishment and growth in affected mice, prolonging their survival. Besides, regulatory T (Treg) and T helper (Th) 17 cells are lymphocyte subsets with opposing actions: Th17 are key effector cells, while Treg are essential cells for immunologic tolerance. Hence, their balance has been implicated in the development of inflammatory, autoimmune and neoplastic processes. Here, we aim to disclose the effect of T3-stimulated DCs in the homeostasis between these pro-inflammatory/regulatory profiles. Methods: Mice bone marrow derived DCs were pulsed with T3 (5nM) for 18 h. Intracellular and secreted cytokine production was assayed by flow cytometry and ELISA, respectively. The ability of DC to stimulate allogenic splenocytes was assessed in a mixed lymphocyte reaction and the expression of different profiles markers was analyzed by flow cytometry. Results / Discussion: T3 stimulated DC production of the Th17-skewing cytokines IL-6, IL-23 and IL-1β. In accordance, allogenic splenocytes co-cultured with T3-matured DCs secreted higher levels of IL-17. The augmented IL-17 production was mainly derived from γδ T cells, although Th17 cells were also involved. On the other hand, T3 reduced the expression of programmed death ligand-1 (PD L1) in DCs, an inhibitory molecule associated with immune tolerance. In agreement, T3-treated DC decreased the frequency of Treg cells, revealed by a reduction of CD4+CD25+FoxP3+ cells. Conclusion: These results reinforce the critical role of T3 in the regulation and maintenance of immune homeostasis since T3-activated DCs favor the promotion of adaptive immunity towards a pro-inflammatory profile. Our findings may be exploited to manipulate the immunogenic potential of DCs to positively regulate the development of protective immunity or negatively control the generation of autoimmune diseases.