Research Article: Regulatory Function of a Novel Population of Mouse Autoantigen-Specific Foxp3− Regulatory T Cells Depends on IFN-γ, NO, and Contact with Target Cells

Date Published: November 17, 2009

Publisher: Public Library of Science

Author(s): Cyndi Chen, Chih-Pin Liu, Derya Unutmaz.

Abstract: Both naturally arising Foxp3+ and antigen-induced Foxp3− regulatory T cells (Treg) play a critical role in regulating immune responses, as well as in preventing autoimmune diseases and graft rejection. It is known that antigen-specific Treg are more potent than polyclonal Treg in suppressing pathogenic immune responses that cause autoimmunity and inflammation. However, difficulty in identifying and isolating a sufficient number of antigen-specific Treg has limited their use in research to elucidate the mechanisms underlying their regulatory function and their potential role in therapy.

Partial Text: Inflammation plays a central role during the development of autoimmune diseases. It is known that CD4+ regulatory T cells (Treg) are able to induce effective immune tolerance that inhibits such inflammatory responses [1], [2], [3], [4]. Defective development or depletion of Treg in animals, such as the naturally arising Foxp3+CD4+CD25+ Treg (nTreg), results in the development of autoimmune diseases, including type 1 diabetes (T1D) [1], [2], [3], [4], [5], [6], [7]. Administration of Treg, expanded in vitro, to animals has been shown to inhibit autoimmune diseases, including T1D [8], [9]. Previous studies have demonstrated that different cell populations with varied phenotypes can function as Treg, regulating both immunity and autoimmunity [10], [11], [12], [13], [14]. Both Foxp3+ and Foxp3− Treg may play a pivotal role in the negative regulation of immune system function and inhibition of inflammation, as well as in the prevention of autoimmune diseases and graft rejection. Therefore, the use of Treg as a cellular therapy to induce immune tolerance in animals or humans may be a promising method to control inflammation and autoimmune diseases.

We report here a novel population of Foxp3-negative GAD p286-specific NR286 Treg isolated from NOR mice. While Th1-like NR286 T cells secreted significant amounts of IFN-γ, they functioned as Treg. Their regulatory function was dependent not only on IFN-γ, but also on NO and cell-contact with target cells. Similar to Foxp3-expressing CD4+CD25+ nTreg, NR286 Treg expressed CD25 and were cell-contact dependent; however, they did not express Foxp3. In addition, separating NR286 Treg cells from target T cells abolished both NO production and suppression of target T cells, regardless of whether IFN−γ was produced in cell cultures. These results showed that production of IFN−γ alone by antigen-activated pathogenic T cells, such as BDC2.5 T, was insufficient to induce NO production unless Treg, such as NR286 T cells, were also present.



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