Mueller, DL. Mechanisms maintaining peripheral tolerance. Nat Immunol 11: 21-27

Department of Medicine and Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Nature Immunology (Impact Factor: 20). 01/2010; 11(1):21-7. DOI: 10.1038/ni.1817
Source: PubMed


The presentation of self-peptide-MHC complexes in the periphery to potentially autoreactive T cells that have escaped negative selection in the thymus poses an important problem to the immune system. In this review, I discuss data that reveal barriers preventing peripheral T cell recognition of self-peptide-MHC complexes, as well as the physiological mechanisms that ensure the elimination or functional inactivation (anergy) of T cells that do come to recognize self-peptide-MHC and threaten the health of the individual.

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    • "Evidence suggests that autoreactive T cells are commonly present in the healthy immune repertoire, but are kept in check by numerous tolerance mechanisms. Although several details of the tolerance mechanisms have yet to be elucidated, mechanisms including negative selection of autoreactive T cells in the thymus, ignorance, anergy, cytokine immune deviation, tolerogenic antigen presenting cells and induction of regulatory cells have been demonstrated to be involved in mediating self-tolerance [1], [2]. Understanding the mechanisms of self-tolerance, which limits the aberrant activation of self-reactive T cells, is crucial for the development of strategies to treat autoimmune diseases, like Multiple sclerosis (MS). "
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    ABSTRACT: Myelin-specific, pro-inflammatory TH17 cells are widely regarded as the drivers of experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple sclerosis (MS). The factors, responsible for the generation and maintenance of TH17 cells as well as their participation in the pathogenic cascade leading to the demyelinating disease, have been studied extensively. However, how these harmful autoreactive cells are controlled in vivo remains unclear. By comparing TCR transgenic mice on a disease susceptible and a disease resistant genetic background, we show here that pathogenic TH17 cells are sequestered within the intestine of spontaneous EAE resistant B10.S mice. Disease resistant B10.S mice harbored higher frequencies of TH17 cells in the intestine compared to EAE susceptible SJL/J mice. Moreover, transferred TH17 cells selectively migrated to intestinal lymphoid organs of B10.S mice. The sequestration of TH17 cells in the gut was partially dependent on the gut homing receptor α4β7-mediated adhesion to the intestine. Administration of α4β7 blocking-antibodies increased the peripheral availability of TH17 cells, resulting in increased EAE severity after immunization in B10.S mice. Together, these results support the concept that the intestine is a check-point for controlling pathogenic, organ-specific T cells.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Recessive peripheral tolerance includes T cell anergy and deletion , and both mechanisms may contribute to self-tolerance [2]. Both CTLA-4 and PD-1 were implied in mediating anergy [36e38]. "
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    ABSTRACT: A major concept in autoimmunity is that disruption of Foxp3(+) regulatory T cells (Tregs) predisposes to breach of tolerance. This is exemplified by the Foxp3-linked disorder termed IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) which affects newborn children. There has been considerable clinical interest in the role of non-depleting anti-CD4 antibodies as a means of upregulating the function of Foxp3(+) Tregs in order to control detrimental inflammatory responses such as transplant rejection. However, according to the paradigm of a Treg-dependent mechanism of action, the effectiveness of anti-CD4 antibodies as a therapy for human autoimmune diseases is unclear considering that Treg function might be intrinsically impaired. Specifically, anti-CD4 therapy is expected to fail in patients suffering from the IPEX syndrome due to the lack of functional Foxp3(+) Tregs. Taking advantage of natural Foxp3 mutant scurfy (sf) mice closely resembling the IPEX syndrome, and genetically engineered mice depleted of Foxp3(+) Tregs, we report here that anti-CD4 treatment induces tolerance independent of Foxp3(+) Tregs. This so far undefined mechanism is dependent on the recessive non-infectious tolerization of autoreactive T cells. Treg-independent tolerance alone is powerful enough to suppress both the onset and severity of autoimmunity and reduces clinically relevant autoantibody levels and liver fibrosis. Mechanistically, tolerance induction requires the concomitant activation of autoreactive T cells and is associated with the down-regulation of the co-stimulatory TNF-receptor superfamily members OX40 and CD30 sustaining CD4(+) T cell survival. In the light of ongoing clinical trials, our results highlight an unexpected potency of anti-CD4 antibodies for the treatment of autoimmune diseases. Particularly, CD4 blockade might represent a novel therapeutic option for the human IPEX syndrome.
    Full-text · Article · Sep 2013 · Journal of Autoimmunity
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    • "Tissue resident DCs, as well as apoptotic cells, which arise in the course of everyday tissueturnover and regeneration, play a central role in the maintenance of peripheral tolerance. DCs internalize apoptotic cell-derived material, process the engulfed auto-antigens, and migrate to the draining lymph nodes, where they inhibit autoreactive effector T cell function via several mechanisms , including anergy induction and peripheral deletion [11]. Notably, the tolerogenic nature of the DCs is crucially shaped by the presence of apoptotic cells. "
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    ABSTRACT: "The enemy of my enemy is my friend." According to this motto, the human protagonists in Paul W. S. Anderson's science-fiction movie "Alien vs. Predator" (2004) solidarize with a predator in order to fight the aliens. Can this ancient and simple logic be transferred to the field of oncology and cancer immunotherapy? Can we utilize mechanisms known from the context of autoimmunity to fight cancer? Here, we summarize immune cell-mediated detection of danger and damage, central and peripheral tolerance, immunoregulation and immune privilege - processes known to be deregulated in the context of autoimmunity. We discuss them with special regard towards their misusage by tumors and pathogens and how they might be instrumentalized in the context of anti-cancer immunotherapy.
    Full-text · Article · May 2013 · Autoimmunity
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