SOCS1 Is a Key Molecule That Prevents Regulatory T Cell Plasticity under Inflammatory Conditions

• Published in: The Journal of immunology (1950) Vol. 199; no. 1; pp. 149 - 158
• Main Authors: Takahashi, Reiko, Nakatsukasa, Hiroko, Shiozawa, Shunichi, Yoshimura, Akihiko
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01.07.2017
• Subjects: Animals; Antigen-presenting cells; CD28 antigen; CD3 antigen; Cell culture; Cell fate; Cell Plasticity; Cytokines; Cytokines - immunology; Dermatitis; Fate maps; Forkhead Transcription Factors - deficiency; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Helper cells; Immunoregulation; Inflammation; Inflammation - immunology; Interferon; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Interleukin 12; Lymphadenopathy; Lymphocytes; Lymphocytes T; Mice; Mice, Knockout; Phosphorylation; RAG2 protein; Rodents; Splenomegaly; Splenomegaly - immunology; Stat4 protein; Suppressor of Cytokine Signaling 1 Protein - deficiency; Suppressor of Cytokine Signaling 1 Protein - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - physiology; γ-Interferon
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600441

We previously showed that regulatory T cells (Tregs) from T cell-specific -deficient mice ( mice) easily convert into Th1- or Th17-like cells (ex-Tregs), which lose Foxp3 expression and suppressive functions in vivo. Because Tregs in mice are constantly exposed to a large amount of inflammatory cytokines produced by non-Tregs in vivo, in this study we analyzed Treg-specific -deficient mice ( mice). These mice developed dermatitis, splenomegaly, and lymphadenopathy that were much milder than those in mice. A fate mapping study revealed that deficiency accelerated the conversion of Tregs to Foxp3 IFN-γ ex-Tregs in the tumor microenvironment and suppressed tumor growth. When transferred into mice, Tregs from mice easily lost Foxp3 expression, whereas those from mice maintained Foxp3 expression. Although Tregs from mice produced IFN-γ after a 3-d culture in response to anti-CD3/CD28 Ab stimulation in vitro, Tregs from mice did not. This finding suggested that the inflammatory conditions in mice modified the born nature of -deficient Tregs. To investigate this mechanism, Tregs from mice were cultured with APCs from mice. These APCs facilitated STAT4 phosphorylation, IFN-γ production, and loss of Foxp3 expression in Tregs from mice in an IL-12-dependent manner. The results indicate that -deficient Tregs tend to convert into ex-Tregs under the inflammatory conditions in which APCs are highly activated, and that SOCS1 could be a useful target for enhancement of anti-tumor immunity.