Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes.
ABSTRACT Regulatory T cells (Tregs) constitute an attractive therapeutic target given their essential role in controlling autoimmunity. However, recent animal studies provide evidence for functional heterogeneity and lineage plasticity within the Treg compartment. To understand better the plasticity of human Tregs in the context of type 1 diabetes, we characterized an IFN-γ-competent subset of human CD4(+)CD127(lo/-)CD25(+) Tregs. We measured the frequency of Tregs in the peripheral blood of patients with type 1 diabetes by epigenetic analysis of the Treg-specific demethylated region (TSDR) and the frequency of the IFN-γ(+) subset by flow cytometry. Purified IFN-γ(+) Tregs were assessed for suppressive function, degree of TSDR demethylation, and expression of Treg lineage markers FOXP3 and Helios. The frequency of Tregs in peripheral blood was comparable but the FOXP3(+)IFN-γ(+) fraction was significantly increased in patients with type 1 diabetes compared to healthy controls. Purified IFN-γ(+) Tregs expressed FOXP3 and possessed suppressive activity but lacked Helios expression and were predominately methylated at the TSDR, characteristics of an adaptive Treg. Naive Tregs were capable of upregulating expression of Th1-associated T-bet, CXCR3, and IFN-γ in response to IL-12. Notably, naive, thymic-derived natural Tregs also demonstrated the capacity for Th1 differentiation without concomitant loss of Helios expression or TSDR demethylation.
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ABSTRACT: Autoimmune disease results from the dysregulation of basic tolerogenic processes designed to control self/non-self-discrimination. Approaches to treat autoimmunity have focused historically on potent immunosuppressives that block the activation and expansion of antigen-specific T cells before they differentiate into pathogenic T cell responses. These therapies are very efficient in reducing clonal expansion and altering early signaling pathways. However, once the pathogenic responses are established (i.e., autoimmunity), the interventions are less effective on activated and differentiated T cell subsets (including memory T cells) or acting in the presence of an inflammatory milieu to abort immune responses at the target tissue and systemically. Moreover, the current immunotherapies require continuous use because they do not redirect the immune system to a state of tolerance. The continuous treatment leads to long-term toxicities and can profoundly suppress protective immune responses targeted at viruses, bacteria, and other pathogens. Over the past decade, there have been tremendous advances in our understanding of the basic processes that control immune tolerance. Among the most exciting has been the identification of a professional regulatory T cell subset that has shown enormous potential in suppressing pathologic immune responses in autoimmune diseases, transplantation, and graft vs. host disease. In this review, we summarize current efforts to induce and maintain tolerance in the autoimmune diabetes setting by using therapeutic vaccination with CD4(+)CD25(+) regulatory T cells. Emphasis will be placed on approaches to exploit regulatory T cells either directly or through the use of anti-CD3 immunotherapy.Proceedings of the National Academy of Sciences 11/2004; 101 Suppl 2:14622-6. · 9.68 Impact Factor
Article: Treg in type 1 diabetes.[show abstract] [hide abstract]
ABSTRACT: At the time of this writing, a major void exists; the lack of a method to prevent and/or reverse type 1 diabetes in humans. We believe this void to a large extent is the result of our lack in understanding the mechanisms of autoimmunity that underlie beta cell destruction, a failure to understand the immunologic factors that contribute to type 1 diabetes, and the absence of immunologic tools which would allow for a better understanding of the mechanisms underlying disease development and monitoring of therapeutic interventions. Due to this, an intense degree of research interest has recently been generated to understand the mechanisms that regulate the immune response and form a state of immunological tolerance. While some progress has been made towards these goals, additional investigations are needed to address the aforementioned knowledge voids including the role for regulatory T cells (Treg), defined by their co-expression of CD4 and CD25 as well as the transcription factor FOXP3, in the pathogenesis and natural history of type 1 diabetes. We and others have recently reported findings related to the frequency and function of Treg cells in type 1 diabetes, yet the resulting literature represents a somewhat conflicting body of findings. Our studies did not support the notion that altered Treg frequencies are associated with type 1 diabetes, but rather did identify alterations in the functional (i.e., suppressive) activities of these cells in subjects with the disease. The need to bring resolution to the aforementioned published discrepancies in frequency and function of Treg in type 1 diabetes represents the impetus for this critical review. In addition, we hope to highlight the need for expanded studies that address specific knowledge gaps regarding the cellular and molecular mechanism(s) related to the frequency and function of Treg.Cell Biochemistry and Biophysics 02/2007; 48(2-3):165-75. · 3.74 Impact Factor