Reduction in regulation

Selective depletion of the CD4⁺CD25⁺ regulatory T (T_Reg)-cell subset in mice induces the spontaneous onset of autoimmune diseases. However, although human CD4⁺CD25^hi T cells can elicit suppressive functions in vitro, there was little evidence of a role for these cells in vivo until a study by Viglietta et al. showed that CD4⁺CD25^hi T cells in patients with multiple sclerosis (MS) have defective regulatory function.

It is easier to activate autoreactive T cells isolated from patients with autoimmune diseases than those from healthy controls. So, the authors set out to compare CD4⁺CD25^hi T_Reg cells isolated from untreated patients with relapsing/remitting MS and healthy control individuals. Initial analysis indicated no differences between the two groups in the level of expression of CD25, or in the frequency of CD4⁺CD25⁺ or CD4⁺CD25^hi T cells in the blood. By contrast, when compared with CD4⁺CD25^hi T_Reg cells purified from healthy controls, CD4⁺CD25^hi T_Reg cells isolated from MS patients were markedly impaired in their ability to suppress CD4⁺CD25⁻ T-cell proliferation and interferon-γ production induced by plate-bound CD3-specific antibody. This lack of suppression resulted from a loss of regulatory function by the CD4⁺CD25^hi T cells and not a defect in the CD4⁺CD25⁻ T cells, as CD4⁺CD25^hi T_Reg cells from healthy individuals were able to suppress autologous CD4⁺CD25⁻ T cells and those derived from MS patients equally. In reciprocal studies, the CD4⁺CD25^hi T_Reg cells from MS patients could not suppress proliferation of CD4⁺CD25⁻ T cells from either healthy individuals or MS patients.

The CD4⁺CD25^hi T_Reg-cell population in MS patients was shown not to be diluted by recently activated cells involved in the ongoing MS-associated immune response in three ways. First, CD4⁺CD25^hi T cells in both MS patients and healthy individuals were anergic; second, the CD4⁺CD25^hiCD62L⁺ cells — which contain no potentially activated CD62L⁻ cells — from MS patients were unable to inhibit CD4⁺CD25⁻ T-cell proliferation; and third, CD4⁺CD25^hi T cells isolated from a healthy individual before and after vaccination against influenza virus — to induce an ongoing immune response — were equally capable of suppressing CD4⁺CD25⁻ T-cell proliferation.

These data provide the first evidence that a defect in CD4⁺CD25^hi T_Reg-cell function can be linked to an autoimmune disease in humans. Further work is needed to determine whether such dysregulation can be viewed as a risk factor for autoimmunity. However, the authors' initial studies showing that CD4⁺CD25^hi T cells from patients with thyroiditis and psoriasis have reduced regulatory function suggest that this hypothesis might hold up.