Editors' ChoiceImmunology

Licensed to Enter

See allHide authors and affiliations

Science Translational Medicine  27 Oct 2010:
Vol. 2, Issue 55, pp. 55ec168
DOI: 10.1126/scitranslmed.3001827

Both autoimmune and allergic diseases are caused by dysregulation of the immune response. Regulatory T cells (Treg cells) can repress the response of other immune cells and, as such, play a central role in the maintenance of immune tolerance and in the prevention of autoimmune and allergic diseases. Foxp3 is the master transcription factor critical for the development and function of Treg cells; Foxp3 deficiency results in an autoimmune syndrome in both mice and humans. However, attempts to treat disease by delivering Foxp3 via virus-mediated gene transfer or transferring Treg cells in vivo have met with limited success thus far. Now, Choi et al. offer a novel therapeutic strategy for autoimmune and allergic disease, constructing and administering a cell-permeable form of the Foxp3 protein.

Choi et al. generated a recombinant fusion protein by joining Foxp3 and a human-derived protein transduction domain peptide. This fusion protein readily penetrated CD4+ T cells and inhibited their proliferation and cytokine production. The intracellular delivery of Foxp3 also converted conventional CD4+ T cells into Treg cells with a suppressor function. In mouse models of Foxp3 deficiency, the systemic administration of the fusion protein ameliorated autoimmune manifestations and improved survival. Furthermore, the local delivery of the Foxp3 fusion protein through intranasal administration substantially decreased allergic airway inflammation.

The therapeutic potential of Treg cells has been investigated in a number of clinical entities, such as autoimmune disorders and allergic diseases, and in the prevention of transplantation rejection. In this study, Choi et al. demonstrated that the nonspecific intracellular delivery of Foxp3 inhibits T cell activation and induces the generation of Treg cells, controlling inflammation in autoimmune and allergic diseases. As protein delivery technologies continue to improve, it is expected that Foxp3 will be able to be targeted specifically to the subset of autoreactive T cells. Targeted delivery would limit global immunosuppression and its unwanted side effects, such as infection and malignancy, and the combination of target delivery with the cell-permeable Foxp3 fusion peptide offers a more clinically acceptable strategy for curtailing undesired immune responses.

J.-M. Choi et al., Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation. Proc. Natl. Acad. Sci. U.S.A. 11 October 2010 (10.1073/pnas.1000400107). [Abstract]

Navigate This Article