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Open Access Publications from the University of California

Regulatory T cell dynamics within chronically inflamed tissue in mouse autoimmune diabetes

  • Author(s): Spence, Allyson
  • Advisor(s): Hermiston, Michelle
  • et al.
Abstract

Regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis and prevention of autoimmunity. In the non-obese diabetic (NOD) mouse model of type 1 diabetes, Tregs accumulate in the inflamed islets of langerhans and delay or prevent the destruction of insulin-producing beta (β) cells. The regulators of Treg homeostasis and function are yet to be completely understood in the context of chronic tissue inflammation. In this work we focused on the specificity of Tregs for their cognate antigen, the dynamics of these Tregs, and influence of the cytokines IL2 and TGFβ. This was accomplished by examining the target tissue compared with peripheral lymphoid sites for different aspects of Treg biology using flow cytometry, histological analysis, and TCR sequencing. We found that islet Tregs were potent mediators of disease prevention, had most recently and strongly been exposed to their cognate antigen, and we could identify a highly activated, antigen specific subset using cell surface markers CD103, ICOS, and TIGIT. Islet Tregs were a dynamic population constantly turning over, but these Tregs were not circulating through the LNs and instead isolated to the tissue. They were specific for known autoantigens, such as insulin, but the highly activated, antigen reactive subset of Tregs were also clonally expanded due to reactivity with unknown islet antigens. After adoptive transfer, both CD103+ and CD103- Tregs prevented diabetes development and were more potent than Tregs from peripheral lymphoid organs. Their efficacy could be increased with a short treatment with IL2. When Tregs cannot respond to TGFβ signaling, their function in preventing diabetes increases, while their ability to prevent autoimmune neuropathy decreases. Overall, our findings that islet Tregs are highly localized, potent effector Tregs that can be manipulated with cytokines implicate the importance of antigen specific tissue Tregs in preventing diabetes development and the impact of Treg cytokine signaling on disease pathogenesis.

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