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.

Figure 3. Therapeutic strategies to restore the balance of pathogenic versus Treg responses in autoimmunity.

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.

Figure 2. Model for self-peptide presentation in shaping T cell function and development of autoimmunity.

Mounting data support a key role for self-antigen presentation in T cell selection and autoimmunity. Left: In the thymus, CD4⁺ T cells with high affinity for self antigens undergo apoptosis (Tconv A) (i), while Tconv B escape negative selection (ii) due to low affinity for “classical” stable peptide MHC (pMHC) complexes that are formed by processing and loading of self-proteins onto MHC class II molecules in late endosomes (iv). Tregs arise from thymocytes that interact with self pMHC complexes with a high affinity insufficient to trigger negative selection (iii) and recognize self-peptides both from homeostasis-related tissue nonspecific antigens (pink rectangles) and from tissue-restricted antigens (yellow rectangles), expressed under the control of Aire in mTECs (iv). Right: In the periphery, positively selected Tregs and Tconvs encounter pMHC complexes that only partially overlap with those presented in the thymus (v). Unstable and/or tissue-specific pMHC complexes (v) may arise when extracellular self-peptides bypass classical processing to associate with MHC class II in early endosomes (yellow triangles). Thus, tTregs recognizing homeostasis antigens can be activated in the periphery (vi), whereas tTregs selected on classical pMHC complexes in the thymus cannot recognize the “peculiar” pMHC complexes uniquely generated in the periphery from the same tissue-restricted antigen (vii). These peculiar pMHC complexes can activate autoreactive cells that escaped negative selection (Tconv B) (viii) as well as pTregs generated in the periphery (ix). Thus, the limited diversity and frequency of tTregs in the tissue, combined with reduced stability and efficacy of pTregs in inflamed tissues, contributes to failure of local immunoregulation of autoreactive Tconv cells and resultant autoimmunity.

Figure 1. Defects in both central and peripheral tolerance contribute to the development of autoimmunity.

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.