T cells in the control of organ-specific autoimmunity
Jeffrey A. Bluestone, … , Mickie Cheng, Mark Anderson
Jeffrey A. Bluestone, … , Mickie Cheng, Mark Anderson
Published May 18, 2015
Citation Information: J Clin Invest. 2015;125(6):2250-2260. https://doi.org/10.1172/JCI78089.
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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 3

Therapeutic strategies to restore the balance of pathogenic versus Treg responses in autoimmunity.

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Therapeutic strategies to restore the balance of pathogenic versus Treg ...
Autoimmune diseases result from an imbalance of pathogenic autoreactive Tconv cells and protective Tregs. Many immunotherapies for autoimmune diseases share a common goal of restoring immune tolerance but employ different strategies to skew the balance of immune responses toward dominant Treg-mediated regulation. Some systemic therapies, such as ATG or alefacept, reset the balance by inducing a massive but selective deletion of Tconvs, including autoreactive T cells. Conversely, more recent approaches such as low-dose IL-2 or Treg cellular therapy are aimed at boosting the number and/or function of Tregs to a point where they are able to control autoreactive T cells. While both types of approaches have been successful in animal models and sporadically in humans, these monotherapies have thus far been largely ineffective at permanently curing autoimmune diseases. This has led to the notion that combination therapies that both eliminate autoreactive T cells and repair Treg defects may be necessary to sufficiently shift the immune scale toward regulation and durably reestablish tolerance.