Thyroid hormone action on dendritic cells drives proinflamatory responses

Beijing

Congreso; 17th International Congress of Immunology; 2019

International Union of Immunology Societies (IUIS)

Background/Aims: Although a cross-talk between immune and endocrine systems has beenwell established, the precise pathways by which these signals co-regulate pro- and antiinflammatoryresponses on antigen-presenting cells remain poorly understood. In this workwe investigated the mechanisms by which triiodothyronine (T3) controls T cell activity viadendritic cell (DC) modulation. Methods: DCs from wild-type (WT) and IL-6-deficient micewere pulsed with T3. Cytokine production and programmed death protein ligands (PD-L) 1 and2 expression were assayed by flow cytometry and ELISA. Interferon-regulatory factor-4 (IRF-4) expression was evaluated by RT-qPCR and flow cytometry. The ability of DCs to stimulateallogenic splenocytes was assessed in a mixed lymphocyte reaction and the different profilemarkers were analyzed by flow cytometry and ELISA. For in vivo experiments, DCs treated withovalbumin and T3 were injected into OTII mice. Proliferation, cytokine production, frequencyof FoxP3+ regulatory T (Treg) cells and PD-1+ cells were determined by MTT assay, ELISAand flow cytometry, respectively. Results: T3 endows DCs with pro-inflammatory potentialcapable of generating IL-17-dominant responses and down-modulating expression of PD-L1and 2. T3-stimulated WT-DCs increased the proportion of IL-17-producing splenocytes, aneffect which was eliminated when splenocytes were incubated with T3-treated DCs derivedfrom IL-6-deficient mice. Enhanced IL-17 expression was recorded in both, CD4- and CD4+populations and involved the IRF-4 pathway. Particularly, gd-T cells but not natural killer (NK), NKT, B lymphocytes nor CD8+ T cells were the major source of IL-17-production from CD4-cells. Moreover, T3-conditioned DCs promoted a decrease of the FoxP3+ Treg population.Furthermore, T3 down-modulated PD-1 expression on CD4- cells thereby limiting inhibitorysignals driven by this co-inhibitory pathway. Thus, T3 acts at the DC level to drive proinflammatoryresponses in vitro. Accordingly, we found that T3 induces IL-17 and IFNg-dominant antigen-specific responses in vivo. Conclusion: These results emphasize therelevance of T3 as an additional immune-endocrine checkpoint and a novel therapeutic targetto modulate IL-17-mediated pro-inflammatory responses.