Background/Purpose: Suppression of autoimmunity or inflamation by regulatory T cells (Tregs) is now well established, recently, natural Foxp3⁺T cells have been shown to be a heterogeneous population consisting of a committed Treg lineage and an uncommitted subpopulation with developmental plasticity. Tregs have been reported to convert into Th1- or Th17-like cells (exFoxp3 cells) under lymphopenic or inflammatory conditions, which might be one of causes of autoimmunity. SOCS1 is defined as an important mechanism for the negative regulation of the cytokine-JAK-STAT pathway. SOCS1-deletion specifically in T cells (LckCre-SOCS1-flox mice) or Tregs (Foxp3Cre-SOCS1-flox mice) induced lupus-like phenomenon such as dermatitis, splenomegaly and lymphoadenopathy, suggesting a defective Treg function in these mice.

We examined the role of SOCS1 to maintain the Foxp3 expression or suppressive functions in natural Tregs.

Methods:

^•Natural Tregs (CD3⁺CD4⁺CD25⁺Foxp3^GFP) from LN of wild type (WT), LckCre-SOCS1-flox, or Foxp3Cre-SOCS1-flox mice sorted by flowcytometry

•Transfer of Treg cells with naïve T cells into Rag2^-/-mice

•Single transfer of Tregs into Rag2^-/-mice

•Tregs cultured with CD3/CD28 or antigen presenting cells in vitro

Results:

1) SOCS1^+/+ Tregs from WT mice efficiently suppressed colitis induced by naive CD4⁺ T cell transfer into Rag2^-/- mice, however, SOCS1^-/- Tregs from LckCre-SOCS1-flox mice could not prevent it (n=3). Only SOCS1^-/- Tregs transferred into Rag2^-/- mice caused colitis, lost Foxp3 expression more rapidly, and converted into IFNγ-producing cells accompanying with hyperactivation of STAT1 (n=3). Foxp3 was stable in IFNγ^-/-SOCS1^-/-Tregs (n=3).

2) Because Tregs from LckCre-SOCS1-flox mice were constantly exposed to inflammatory cytokines from non-Treg cells in vivo, we then analyzed Treg specific SOCS1 deficient mice (Foxp3Cre-SOCS1-flox). Tregs from Foxp3Cre-SOCS1-flox mice maintained Foxp3 expression transferred into Rag2^-/-mice, on the contrary, those from LckCre-SOCS1-flox mice (n=3).

3) Tregs from LckCre-SOCS1-flox mice produced IFNγ after culture with CD3/CD28 in vitro, however, Tregs from Foxp3Cre-SOCS1-flox mice did not (n=3). When Tregs from Foxp3Cre-SOCS1-flox mice were cultured with antigen presenting cells (APCs) from LckCre-SOCS1-flox mice, they produced IFNγ, which was blocked by anti-IL-12 antibodies (n=3).

Conclusion: SOCS1 plays important roles in maintaining Foxp3 expression and is necessary for suppression activity of Tregs by regulating STAT1 under inflammatory conditions in which APCs are highly activated.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/socs1-is-one-of-the-key-molecules-to-prevent-the-plasticity-of-regulatory-t-cells-and-the-development-of-autoimmunity/