Cytokines 2017

Suppressors of cytokine signaling 1 (SOCS1) is defined as an important molecule for the negative regulation of the cytokine-JAK-STAT pathway. To elucidate the role of SOCS1 in regulatory T cells (Tregs), we analyzed Treg-specific Socs1-deficient mice, Socs1^fl/flFoxp3^YFP-Cre mice. In the mice, Socs1 genomes are deleted in Foxp3-expressing Tregs and also in exTregs which expressed Foxp3 only transiently. These mice developed mild dermatitis, splenomegaly, and lymphadenopathy. Fate mapping study elucidated that Socs1^-/- Tregs easily converted to Foxp3^-IFNγ⁺ exTregs in the tumor microenvironment and suppressed the tumor growth. Further, among the tumor-infiltrating lymphocytes, conversion to exTregs was significantly increased in Socs1^-/- Tregs compared with Socs1^+/+ Tregs, while the conversion-rate was equivalent between Socs1^-/- Tregs and Socs1^+/+ Tregs in the draining LNs. To investigate the mechanism of plasticity of Socs1^-/- Tregs, Tregs from Socs1^fl/flFoxp3^YFP-Cre mice were cultured with antigen-presenting cells (APCs) from T cell-specific Socs1-deficient mice, which were exposed to a lot of inflammatory cytokines. These APCs caused STAT4 phosphorylation and loss of Foxp3 expression in Tregs from Socs1^fl/flFoxp3^YFP-Cre mice, which was blocked by anti-IL-12 antibodies. These results indicate that Socs1^-/- Tregs have a tendency to convert into exTregs under the inflammatory conditions where APCs are highly activated. In autoimmune conditions, Tregs from lupus prone mice, MRL/lpr mice easily converted to Foxp3^-IFNγ⁺ exTregs after culture with CD3/CD28. The Treg plasticity might be due to the abnormal expression of SOCS1 or STAT4, which are reported as one of the pathogenesis of lupus. In conclusion, SOCS1 is one of the key molecules that may protect Tregs from conversion to exTregs under the inflammatory settings such as cancer or autoimmunity, and we suggest that the upregulation of SOCS1 in Tregs at appropriate levels maintains Treg functions.