Abstract
Peripheral immune tolerance requires a finely controlled balance between tolerance to self-antigens and protective immunity against enteric and invading pathogens. Self-reactive T cells sometimes escape thymic clonal deletion, and can subsequently provoke autoimmune diseases such as type 1 diabetes (T1D) unless they are controlled by a network of tolerance mechanisms in the periphery, including CD4+ regulatory T cells (Treg) cells. CD4+ Treg cells are characterized by the constitutive expression of the IL-2Rα chain (CD25) and preferentially express the forkhead winged helix transcriptional regulator Foxp3. These cells have been shown to possess immunosuppressive properties towards various immune cell subsets and their defects are thought to contribute to many autoimmune disorders. Strong evidence shows that IL-2 is one of the important stimulatory signals for the development, function and fitness of Treg cells. The non-obese diabetic (NOD) mouse model, a prototypic model of spontaneous autoimmunity, mimics many features of human T1 D. Using this model, the contribution of the IL-2-IL-2R pathway to the development of T1 D and other autoimmune disorders has been extensively studied. In the past years, strong genetic and molecular evidence has indicated an essential role for the IL-2/IL-2R pathway in autoimmune disorders. Thus, the major role of IL-2 is to maintain immune tolerance by promoting Treg cell development, functional fitness and stability. Here we first summarize the genetic and experimental evidence demonstrating a role for IL-2 in autoimmunity, mainly through the study of the NOD mouse model, and analyze the cellular and molecular mechanisms of its action on Treg cells. We then move on to describe how this data can be translated to applications for human autoimmune diseases by using IL-2 as a therapeutic agent to restore Treg cell fitness, numbers and functions.
Highlights
Peripheral immune tolerance requires a finely controlled balance between maintaining tolerance to self-antigens and mounting protective immunity against enteric and invading pathogens [1]
Self-reactive T cells sometimes escape thymic clonal deletion, and can subsequently provoke autoimmune diseases such as type 1 diabetes (T1D) unless they are controlled by a network of tolerance mechanisms in the periphery, including CD4+ regulatory T cells (Treg) cells [2]
The increased transcriptional activity of protective Idd3 alleles translates into higher levels of IL-2 production by auto-reactive CD8+ T cells in response to antigenic stimulation and, controls the size of the Treg cell pool in the pancreatic lymph nodes of non-obese diabetic (NOD) mice [10,22] These results show that IL-2 gene variation may affect the balance between islet-specific auto-reactive T cells and Foxp3+ Treg cells, and precipitate T1 D
Summary
Peripheral immune tolerance requires a finely controlled balance between maintaining tolerance to self-antigens and mounting protective immunity against enteric and invading pathogens [1]. The local inflammatory micro-environment or the degree of functional Treg ablation are contributing factors which may unveil this Treg defect, and in turn, mark the transition to overt autoimmunity; and 2) the autoantigen-specific Treg cell pool remain unaffected but genetic variation influences immune selection and/or activation of antigen-specific, pathogenic T cells, leading to a breakdown of self tolerance in a given organ. These two scenarios are non mutually-exclusive in individual subjects. A deeper understanding of the factors that modulate this phenotypic and functional plasticity in Foxp3+ Treg cells will be needed in order to implement Treg-cell based therapies in autoimmune disease
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