Abstract
CD4+CD25hi T cells are thought to be crucial for the maintenance of immunological tolerance to self antigens. In this study, we investigated the frequencies of these cells in the early stage of type 1 diabetes, as well as in a setting of possible pre-diabetic autoimmunity. Hence, the expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi T cells was analyzed using flow cytometry in 14 patients with recent onset type 1 diabetes, in 9 at-risk individuals, and 9 healthy individuals with no known risk for type 1 diabetes. Our results show there were no differences in the frequency of CD4+CD25hi cells between groups. However, compared to controls, recent-onset type 1 diabetic patients had higher expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi cells from peripheral blood. The median fluorescence intensity of FOXP3 was significantly higher in CD4+CD25hi cells from patients with type 1 diabetes than from controls. Furthermore, a positive correlation between the frequency of FOXP3+ cells and the median fluorescence intensity of FOXP3 was observed among patients with type 1 diabetes. These data suggest that the frequency of CD4+CD25hi FOXP3+ T cells in the periphery is not decreased but rather increased at onset of type 1 diabetes. Thus, functional deficiencies rather than reduced numbers of CD4+CD25hi cells could contribute to the development of type 1 diabetes.
Highlights
There is little doubt today that a regulatory subset of T cells necessary for peripheral tolerance exists, and that absence of these cells causes autoimmunity in a variety of experimental settings [1]
To determine the frequency of cells with a Treg phenotype, we compared the percentages of CD4+CD25hi cells expressing FOXP3, CTLA-4, and CD27 determined by FACS
Gated cells were analyzed for expression of FOXP3, CTLA-4, and CD27 (Figure 1(c))
Summary
There is little doubt today that a regulatory subset of T cells necessary for peripheral tolerance exists, and that absence of these cells causes autoimmunity in a variety of experimental settings [1]. Activation of human T cells induces transient expression of FOXP3 in non-regulatory T cells without conferring a regulatory phenotype to the affected cells [5,6,7,8,9]. Some report this phenomenon to be a consequence of T cell receptor (TCR) stimulation [7], while others have postulated that TCR stimulation does not produce FOXP3 expression at either gene or protein level [10]. CTLA-4 is a costimulatory molecule with potent suppressive function constitutively expressed on Treg and on activated effector T cells [11,12]. Other evidence suggests that Treg expressing CD27 are more suppressive than CD27-negative counterparts [16]
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