Inhibins regulate peripheral regulatory T cell induction through modulation of dendritic cell function

• Published in: FEBS open bio 2019-01, Vol.9 (1), p.137-147
• Main Authors: Fuente‐Granada, Marisol, Olguín‐Alor, Roxana, Ortega‐Francisco, Sandra, Bonifaz, Laura C., Soldevila, Gloria
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Bone marrow; CD103 antigen; CD11c antigen; Cell activation; Cells, Cultured; Cytokines; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Gene expression; Growth factors; Homeostasis; Hypersensitivity (delayed); Immunological tolerance; Inhibin; inhibins; Inhibins - deficiency; Inhibins - metabolism; Kinases; Lamina propria; Lipopolysaccharides; Lymph nodes; Lymphatic system; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; PD-L1 protein; peripheral tolerance; Spleen; T cell receptors; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tregs
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12555

We have previously reported that the absence of inhibins results in impaired dendritic cell (DC) maturation and function, leading to decreased T cell activation and diminished delayed‐type hypersensitivity responses. Here, we investigated the role of inhibins in peripheral regulatory T cell (Treg) induction in vitro and in vivo. Inhibin deficient (Inhα−/−) mice showed an increased percentage of peripherally induced Tregs in colonic lamina propria and mesenteric lymph nodes, compared to Inhα+/+ mice, which correlated with increased expression of PD‐L1 in CD103+ and CD8α+ DCs. Lipopolysaccharide‐stimulated bone marrow‐derived and ex vivo spleen‐ and lymph node‐purified CD11c+ Inhα−/− DCs induced higher Tregs in vitro. Moreover, in vivo anti‐DEC205‐ovalbumin (OVA) DC targeting of mice with adoptively transferred OVA‐specific T cells showed enhanced induced peripheral Treg conversion in Inhα−/− mice. These data identify inhibins as key regulators of peripheral T cell tolerance. Dendritic cells (DCs) play a key role in the induction of peripherally induced regulatory T cells (Tregs) under homeostatic and inflammatory conditions. This study demonstrates that inhibins modulate the induction of Tregs from naïve T cells in the periphery through promoting DC maturation and function. Inhibin‐deficient DCs showed increased levels of PD‐L1, correlating with increased induction of Tregs in vitro and in vivo.