Editors' ChoiceMultiple Sclerosis

OutFOXing Tolerance in Multiple Sclerosis

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Science Translational Medicine  11 May 2011:
Vol. 3, Issue 82, pp. 82ec71
DOI: 10.1126/scitranslmed.3002599

Regulatory T cells (Treg cells) are a specialized subset of lymphocytes that prevent autoimmune disease by suppressing misdirected immune responses to the patient’s own body. Because Treg cells are critical for maintaining tolerance to self-antigens, they have become an exciting therapeutic target for treating autoimmunity. However, Treg cells may be more heterogeneous than previously thought and, indeed, may show phenotypic plasticity. Specifically, several studies done in mice demonstrate that Treg cells can secrete cytokines that are typically associated with autoimmune damage, such as interferon-γ (IFN-γ). Now, Dominguez-Villar et al. provide support for these important animal findings in human disease.

The investigators examined Treg cells in patients with relapsing remitting multiple sclerosis (RRMS), an inflammatory disorder in which autoreactive lymphocytes are thought to attack and damage the myelin required for nerve cell communication in the brain and spinal cord. Dominguez-Villar et al. identified Treg cells by their characteristic transcription factor, Foxp3, as well as previously defined cell surface markers. When they stimulated Treg cells from untreated patients ex vivo, they found that the number of Treg cells secreting IFN-γ was significantly higher than in healthy controls and that these cells up-regulated transcripts normally found in pathogenic effector cells. They then examined the Treg cells of patients treated with IFN-β, a disease-modifying therapy that affects the IFN-γ secretion pathway through inhibition of the inflammatory cytokine IL-12. The frequency of Treg cells secreting IFN-γ in treated patients was decreased to numbers similar to those of healthy controls. In support of a role for IL-12 inhibition in this finding, the authors showed that they could induce Treg cells from healthy subjects to secrete IFN-γ by culturing them in the presence of IL-12. Importantly, they demonstrated that Foxp3+ Treg cells that secrete IFN-γ are less effective at suppressing immune responses. These data provide a potential mechanism for how inflammatory conditions can change the phenotype of Treg cells and impair their function, a process that may be important for disease pathogenesis. In addition, these findings will have important implications for determining which Treg populations might be most effective for treating patients and, therefore, will lay the groundwork for identifying factors that promote Treg functional stability.

M. Dominguez-Vellar et al., Identification of T helper type 1–like, Foxp3+ regulatory T cells in human autoimmune disease. Nat. Med. 3 May 2011 (10.1038/nm.2389). [Abstract]

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