TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity

• Published in: PloS one Vol. 8; no. 9; p. e74639
• Main Authors: Muto, Go, Kotani, Hitoshi, Kondo, Taisuke, Morita, Rimpei, Tsuruta, Sanae, Kobayashi, Takashi, Luche, Hervé, Fehling, Hans Joerg, Walsh, Matthew, Choi, Yongwon, Yoshimura, Akihiko
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.09.2013; Public Library of Science (PLoS)
• Subjects: Adaptive immunity; Adoptive transfer; Animals; Antigens; Arthritis; Autoimmune diseases; Autoimmunity; Autoimmunity - immunology; Cell fate; Cell Proliferation; Clonal deletion; Colitis; Comparative analysis; Conversion; Cytokines; Development and progression; Fate maps; Female; Flox; Forkhead Transcription Factors - metabolism; Foxp3 protein; Homeostasis; Immunity; Immunoglobulin E; Immunology; Immunoregulation; Inflammation; Integrases - metabolism; Interleukin-2 - metabolism; Kinases; Laboratories; Lymphadenopathy; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lymphopenia; Medicine; Mice; Mice, Knockout; Phenotype; RAG2 protein; Receptors; Rheumatoid arthritis; Skin diseases; STAT5 Transcription Factor - metabolism; T cell receptors; T cells; T-cell receptor; T-Lymphocytes, Regulatory - immunology; Th2 Cells - immunology; TNF Receptor-Associated Factor 6 - deficiency; TNF Receptor-Associated Factor 6 - metabolism; TRAF6 protein; Transcription factors; Tumor necrosis factor-TNF; United States > US; Japan; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0074639

Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 (+) Tregs into Rag2(-/-) mice revealed that TRAF6-deficient Tregs converted into Foxp3(-) cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3(+) to Foxp3(-) (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.