T cells in the control of organ-specific autoimmunity
Jeffrey A. Bluestone, Hélène Bour-Jordan, Mickie Cheng, Mark Anderson
Jeffrey A. Bluestone, Hélène Bour-Jordan, Mickie Cheng, Mark Anderson
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Review Series

T cells in the control of organ-specific autoimmunity

Abstract

Immune tolerance is critical to the avoidance of unwarranted immune responses against self antigens. Multiple, non-redundant checkpoints are in place to prevent such potentially deleterious autoimmune responses while preserving immunity integral to the fight against foreign pathogens. Nevertheless, a large and growing segment of the population is developing autoimmune diseases. Deciphering cellular and molecular pathways of immune tolerance is an important goal, with the expectation that understanding these pathways will lead to new clinical advances in the treatment of these devastating diseases. The vast majority of autoimmune diseases develop as a consequence of complex mechanisms that depend on genetic, epigenetic, molecular, cellular, and environmental elements and result in alterations in many different checkpoints of tolerance and ultimately in the breakdown of immune tolerance. The manifestations of this breakdown are harmful inflammatory responses in peripheral tissues driven by innate immunity and self antigen–specific pathogenic T and B cells. T cells play a central role in the regulation and initiation of these responses. In this Review we summarize our current understanding of the mechanisms involved in these fundamental checkpoints, the pathways that are defective in autoimmune diseases, and the therapeutic strategies being developed with the goal of restoring immune tolerance.

Authors

Jeffrey A. Bluestone, Hélène Bour-Jordan, Mickie Cheng, Mark Anderson

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Figure 1

Defects in both central and peripheral tolerance contribute to the development of autoimmunity.

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Defects in both central and peripheral tolerance contribute to the devel...
Left: In healthy individuals, most developing thymocytes with highly self-reactive TCRs are deleted during negative selection, while nonautoreactive cells mature and leave the thymus. Tregs are also selected on self antigens and express TCRs with higher affinity for self antigens than do Tconvs. The presentation of self antigens to developing thymocytes by Aire+ mTECs and thymic DCs is integral to the negative selection of autoreactive T cells and the generation of Tregs. Upon thymic selection, these Tregs migrate to the periphery, where they play a central role in maintaining peripheral tolerance, notably by controlling autoreactive T cells that escaped negative selection. Right: In contrast, in individuals with autoimmune diseases, Tregs demonstrate epigenetic, transcriptional, and functional features of instability that may result in loss of Foxp3 expression and suppressive function. These “ex-Foxp3” cells remain skewed toward autoreactivity and, in the absence of Foxp3 expression, can produce pro-inflammatory cytokines that may contribute to the pathological destruction of peripheral tissues. Moreover, Tregs are inefficient at controlling autoreactive T cells that escaped negative selection and are more prone to activation in the periphery due to defects in presentation of self antigens in the thymus.