IFN-α/β receptor signaling promotes regulatory T cell development and function under stress conditions

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (9), p.4265-4276
• Main Authors: Metidji, Amina, Rieder, Sadiye Amcaoglu, Glass, Deborah Dacek, Cremer, Isabelle, Punkosdy, George A, Shevach, Ethan M
• Format: Article
• Language: English
• Subjects: Animals; Cell Survival - genetics; Chimera; Female; Gene Knockout Techniques; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Interferon Type I - metabolism; Interferon Type I - pharmacology; Interleukin-2 - metabolism; Interleukin-2 - pharmacology; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocyte Count; Male; Mice; Mice, Knockout; Phenotype; Phosphorylation - drug effects; Poly I-C - pharmacology; Receptor, Interferon alpha-beta - metabolism; Signal Transduction - drug effects; Spleen - immunology; Spleen - metabolism; STAT5 Transcription Factor - metabolism; Stress, Physiological; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Thymus Gland - immunology; Thymus Gland - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1500036

Type I IFNs are a family of cytokines with antiviral and immunomodulatory properties. Although the antiviral effects of IFNs are well characterized, their immunomodulatory properties are less clear. To specifically address the effects of type I IFNs on T regulatory cells (Tregs), we studied mixed bone marrow chimeras between wild-type and IFN-α/β receptor (IFNAR) knockout (KO) mice, and heterozygous female mice expressing a Treg-specific deletion of the IFNAR. In these two models, IFNAR signaling promotes the development of the Treg lineage in the thymus and their survival in the periphery. IFNAR KO Tregs had a higher expression of the proapoptotic gene Bim and higher frequency of active caspase-positive cells. IFNAR KO Tregs from chimeric mice displayed a more naive phenotype, accompanied by lower levels of CD25 and phosphorylated STAT5. Therefore, in Tregs, IFNAR signaling may directly or indirectly affect phosphorylation of STAT5. In mixed chimeras with Scurfy fetal liver, Tregs derived from IFNAR KO bone marrow were unable to control T effector cell activation and tissue inflammation. Under stress conditions or in a competitive environment, IFNAR signaling may be required to maintain Treg homeostasis and function.