Immune tolerance and the prevention of autoimmune diseases essentially depend on thymic tissue homeostasis.

The intricate balance of immune reactions towards invading pathogens and immune tolerance towards self is pivotal in preventing autoimmune diseases, with the thymus playing a central role in establishing and maintaining this equilibrium. The induction of central immune tolerance in the thymus involves the elimination of self-reactive T cells, a mechanism essential for averting autoimmunity. Disruption of the thymic T cell selection mechanisms can lead to the development of autoimmune diseases. In the dynamic microenvironment of the thymus, T cell migration and interactions with thymic stromal cells are critical for the selection processes that ensure self-tolerance. Thymic epithelial cells are particularly significant in this context, presenting self-antigens and inducing the negative selection of autoreactive T cells. Further, the synergistic roles of thymic fibroblasts, B cells, and dendritic cells in antigen presentation, selection and the development of regulatory T cells are pivotal in maintaining immune responses tightly regulated. This review article collates these insights, offering a comprehensive examination of the multifaceted role of thymic tissue homeostasis in the establishment of immune tolerance and its implications in the prevention of autoimmune diseases. Additionally, the developmental pathways of the thymus are explored, highlighting how genetic aberrations can disrupt thymic architecture and function, leading to autoimmune conditions. The impact of infections on immune tolerance is another critical area, with pathogens potentially triggering autoimmunity by altering thymic homeostasis. Overall, this review underscores the integral role of thymic tissue homeostasis in the prevention of autoimmune diseases, discussing insights into potential therapeutic strategies and examining putative avenues for future research on developing thymic-based therapies in treating and preventing autoimmune conditions.

Regulatory T Cells for Control of Autoimmunity.

Regulatory T (Treg) cells, which specifically express the master transcription factor FoxP3, are indispensable for the maintenance of immunological self-tolerance and homeostasis. Their functional or numerical anomalies can be causative of autoimmune and other inflammatory diseases. Recent advances in the research of the cellular and molecular basis of how Treg cells develop, exert suppression, and maintain their function have enabled devising various ways for controlling physiological and pathological immune responses by targeting Treg cells. It is now envisaged that Treg cells as a "living drug" are able to achieve antigen-specific immune suppression of various immune responses and reestablish immunological self-tolerance in the clinic.

Restoring tolerance with antigen delivery.

Strategies that modulate antigen delivery are being tested to reverse autoimmunity.

A guide to thymic selection of T cells.

The thymus is an evolutionarily conserved organ that supports the development of T cells. Not only does the thymic environment support the rearrangement and expression of diverse T cell receptors but also provides a unique niche for the selection of appropriate T cell clones. Thymic selection ensures that the repertoire of available T cells is both useful (being MHC-restricted) and safe (being self-tolerant). The unique antigen-presentation features of the thymus ensure that the display of self-antigens is optimal to induce tolerance to all types of self-tissue. MHC class-specific functions of CD4+ T helper cells, CD8+ killer T cells and CD4+ regulatory T cells are also established in the thymus. Finally, the thymus provides signals for the development of several minor T cell subsets that promote immune and tissue homeostasis. This Review provides an introductory-level overview of our current understanding of the sophisticated thymic selection mechanisms that ensure T cells are useful and safe.

Mitochondrial-regulated Tregs: potential therapeutic targets for autoimmune diseases of the central nervous system.

Regulatory T cells (Tregs) can eliminate autoreactive lymphocytes, induce self-tolerance, and suppress the inflammatory response. Mitochondria, as the energy factories of cells, are essential for regulating the survival, differentiation, and function of Tregs. Studies have shown that patients with autoimmune diseases of the central nervous system, such as multiple sclerosis, neuromyelitis optica spectrum disorder, and autoimmune encephalitis, have aberrant Tregs and mitochondrial damage. However, the role of mitochondrial-regulated Tregs in autoimmune diseases of the central nervous system remains inconclusive. Therefore, this study reviews the mitochondrial regulation of Tregs in autoimmune diseases of the central nervous system and investigates the possible mitochondrial therapeutic targets.

Thymic mimetic cells function beyond self-tolerance.

Development of immunocompetent T cells in the thymus is required for effective defence against all types of pathogens, including viruses, bacteria and fungi. To this end, T cells undergo a very strict educational program in the thymus, during which both non-functional and self-reactive T cell clones are eliminated by means of positive and negative selection1.Thymic epithelial cells (TECs) have an indispensable role in these processes, and previous studies have shown the notable heterogeneity of these cells2-7. Here, using multiomic analysis, we provide further insights into the functional and developmental diversity of TECs in mice, and reveal a detailed atlas of the TEC compartment according to cell transcriptional states and chromatin landscapes. Our analysis highlights unconventional TEC subsets that are similar to functionally well-defined parenchymal populations, including endocrine cells, microfold cells and myocytes. By focusing on the endocrine and microfold TEC populations, we show that endocrine TECs require Insm1 for their development and are crucial to maintaining thymus cellularity in a ghrelin-dependent manner; by contrast, microfold TECs require Spib for their development and are essential for the generation of thymic IgA+ plasma cells. Collectively, our study reveals that medullary TECs have the potential to differentiate into various types of molecularly distinct and functionally defined cells, which not only contribute to the induction of central tolerance, but also regulate the homeostasis of other thymus-resident populations.

Towards a quantitative theory of tolerance.

A cornerstone of the classical view of tolerance is the elimination of self-reactive T cells via negative selection in the thymus. However, high-throughput T cell receptor (TCR) sequencing data have so far failed to detect substantial signatures of negative selection in the observed repertoires. In addition, quantitative estimates as well as recent experiments suggest that the elimination of self-reactive T cells is at best incomplete. We discuss several recent theoretical ideas that might explain tolerance while being consistent with these observations, including collective decision-making through quorum sensing, and sensitivity to change through dynamic tuning and adaptation. We propose that a unified quantitative theory of tolerance should combine these elements to help to explain the plasticity of the immune system and its robustness to autoimmunity.

Foxp3+ regulatory T cells in the central nervous system and other nonlymphoid tissues.

Foxp3+ regulatory T (Treg) cells are indispensable for the maintenance of immunologic self-tolerance as well as for the confinement of autoimmune inflammation after the breach of self-tolerance. In order to fulfill these tasks, Treg cells operate in secondary lymphoid tissues and nonlymphoid tissues. The conditions for Treg cell stability and for their modes of action are different according to their compartment of residence. In addition, Treg cells initiate residency programs to inhabit niches in nonlympoid tissues (NLT) in steady state and after re-establishment of previously deflected homeostasis for extended periods of time. These NLT Treg cells are different from lymphoid tissue residing Treg cells and are functionally specialized to subserve not only immune functions but support intrinsic functions of their tissue of residence. This review will highlight current ideas about the functional specialization of NLT Treg cells in particular in the central nervous system (CNS) and discuss challenges that we are facing in an effort to exploit the power of NLT Treg cells for maintenance of tissue homeostasis and perhaps also tissue regeneration.

[Mechanisms of immunological tolerance and their dysregulation in rheumatic diseases]. / Mechanismen immunologischer Toleranz und ihrer Dysregulation bei rheumatischen Erkrankungen.

The major tasks of the immune system are protection against infectious agents, maintaining homeostasis by recognizing and neutralizing noxious substances from the environment, and monitoring pathological, e.g. neoplastic tissue changes. It accomplishes these tasks through complex interactions of cellular and humoral components of the innate and adaptive immune system. This review article focuses on a central problem of self versus non-self discrimination in the development of B and T lymphocytes as carriers of adaptive immunity. During maturation of the lymphocytes in the bone marrow, large repertoires of lymphocyte receptors are randomly generated by somatic recombination, which as a whole have the capability of recognizing any foreign antigen. In order to reduce the implicit risk of autoaggressive immunity that might arise from evolutionary conserved structural motifs in self and foreign antigens, the adaptive immune system must provide redundant mechanisms (clonal deletion, anergy, quiescence and suppression) to eliminate or inactivate lymphocytes expressing highly avid receptors for autoantigens. Thus, the provision of costimulatory signals resulting in a reduced activation threshold of potentially autoreactive anergic T cells through infection, molecular mimicry, disrupted apoptosis regulation, altered "self" by post-translational modification, genetic changes in transcription factors with critical importance for thymic tolerance induction or signaling components of apoptosis can lead to a disruption of self-tolerance and the induction of pathogenic autoimmunity.

The regulation of self-tolerance and the role of inflammasome molecules.

Inflammasome molecules make up a family of receptors that typically function to initiate a proinflammatory response upon infection by microbial pathogens. Dysregulation of inflammasome activity has been linked to unwanted chronic inflammation, which has also been implicated in certain autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and related animal models. Classical inflammasome activation-dependent events have intrinsic and extrinsic effects on both innate and adaptive immune effectors, as well as resident cells in the target tissue, which all can contribute to an autoimmune response. Recently, inflammasome molecules have also been found to regulate the differentiation and function of immune effector cells independent of classical inflammasome-activated inflammation. These alternative functions for inflammasome molecules shape the nature of the adaptive immune response, that in turn can either promote or suppress the progression of autoimmunity. In this review we will summarize the roles of inflammasome molecules in regulating self-tolerance and the development of autoimmunity.

Autoimmunity to the modified self.

Protein posttranslational modifications can break tolerance to the self-proteome.

The link between obesity and autoimmunity.

Overnutrition could lead to loss of self-tolerance by impinging on immune regulation.

Salty Treg cells get out of balance.

Although metabolic rewiring of Treg cells constitutes a hallmark in autoimmune diseases, extrinsic and intrinsic mechanisms that imprint on this re-programming remain poorly understood. In this issue of Cell Metabolism, Côrte-Real and colleagues demonstrate that high salt exposure disturbs the mitochondrial respiration in Treg cells, promoting a pro-inflammatory phenotype, loss of function, and associated breakdown of self-tolerance.

Learning from the nexus of autoimmunity and cancer.

The immune system plays critical roles in both autoimmunity and cancer, diseases at opposite ends of the immune spectrum. Autoimmunity arises from loss of T cell tolerance against self, while in cancer, poor immunity against transformed self fails to control tumor growth. Blockade of pathways that preserve self-tolerance is being leveraged to unleash immunity against many tumors; however, widespread success is hindered by the autoimmune-like toxicities that arise in treated patients. Knowledge gained from the treatment of autoimmunity can be leveraged to treat these toxicities in patients. Further, the understanding of how T cell dysfunction arises in cancer can be leveraged to induce a similar state in autoreactive T cells. Here, we review what is known about the T cell response in autoimmunity and cancer and highlight ways in which we can learn from the nexus of these two diseases to improve the application, efficacy, and management of immunotherapies.

Antigen-specific immunotherapy to restore antigen-specific tolerance in Type 1 diabetes and Graves' disease.

Type 1 diabetes and Graves' disease are chronic autoimmune conditions, characterized by a dysregulated immune response. In Type 1 diabetes, there is beta cell destruction and subsequent insulin deficiency whereas in Graves' disease, there is unregulated excessive thyroid hormone production. Both diseases result in significant psychosocial, physiological, and emotional burden. There are associated risks of diabetic ketoacidosis and hypoglycaemia in Type 1 diabetes and risks of thyrotoxicosis and orbitopathy in Graves' disease. Advances in the understanding of the immunopathogenesis and response to immunotherapy in Type 1 diabetes and Graves' disease have facilitated the introduction of targeted therapies to induce self-tolerance, and subsequently, the potential to induce long-term remission if effective. We explore current research surrounding the use of antigen-specific immunotherapies, with a focus on human studies, in Type 1 diabetes and Graves' disease including protein-based, peptide-based, dendritic-cell-based, and nanoparticle-based immunotherapies, including discussion of factors to be considered when translating immunotherapies to clinical practice.

Stepwise acquisition of unique epigenetic signatures during differentiation of tissue Treg cells.

Regulatory T cells in non-lymphoid tissues are not only critical for maintaining self-tolerance, but are also important for promoting organ homeostasis and tissue repair. It is proposed that the generation of tissue Treg cells is a stepwise, multi-site process, accompanied by extensive epigenome remodeling, finally leading to the acquisition of unique tissue-specific epigenetic signatures. This process is initiated in the thymus, where Treg cells acquire core phenotypic and functional properties, followed by a priming step in secondary lymphoid organs that permits Treg cells to exit the lymphoid organs and seed into non-lymphoid tissues. There, a final specialization process takes place in response to unique microenvironmental cues in the respective tissue. In this review, we will summarize recent findings on this multi-site tissue Treg cell differentiation and highlight the importance of epigenetic remodeling during these stepwise events.

Autoimmunity: Are we asking the right question?

For decades, the main question immunologists have asked about autoimmunity is "what causes a break in self-tolerance?" We have not found good answers to that question, and I believe we are still so ignorant because it's the wrong question. Rather than a break in self-tolerance, I suggest that many autoimmune diseases might be due to defects in normal tissue physiology.

IGF1R signalling is a guardian of self-tolerance restricting autoantibody production.

Objective: Insulin-like growth factor 1 receptor (IGF1R) acts at the crossroad between immunity and cancer, being an attractive therapeutic target in these areas. IGF1R is broadly expressed by antigen-presenting cells (APC). Using mice immunised with the methylated albumin from bovine serum (BSA-immunised mice) and human CD14+ APCs, we investigated the role that IGF1R plays during adaptive immune responses. Methods: The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry. The levels of autoantibody and cytokine production were measured by microarray or conventional ELISA. The transcriptional profile of CD14+ cells from blood of 55 patients with rheumatoid arthritis (RA) was analysed with RNA-sequencing. Results: Inhibition of IGF1R resulted in perifollicular infiltration of functionally compromised S256-phosphorylated FoxO1+ APCs, and an increased frequency of IgM+CD21+ B cells, which enlarged the marginal zone (MZ). Enlargement of MHCII+CD11b+ APCs ensured favourable conditions for their communication with IgM+ B cells in the MZ. The reduced expression of ICOSL and CXCR5 by APCs after IGF1R inhibition led to impaired T cell control, which resulted in autoreactivity of extra-follicular B cells and autoantibody production. In the clinical setting, the low expression of IGF1R on CD14+ APCs was associated with an involuted FOXO pathway, non-inflammatory cell metabolism and a high IL10 production characteristic for tolerogenic macrophages. Furthermore, autoantibody positivity was associated with low IGF1R signalling in CD14+ APCs. Conclusions: In experimental model and in patient material, this study demonstrates that IGF1R plays an important role in preventing autoimmunity. The study raises awareness of that immune tolerance may be broken during therapeutic IGF1R targeting.

Standing on the shoulders of mice.

While inbred mice have informed most of what we know about the immune system in the modern era, they have clear limitations with respect to their ability to be informative regarding genetic heterogeneity or microbial influences. They have also not been very predictive as models of human disease or vaccination results. Although there are concerted attempts to compensate for these flaws, the rapid rise of human studies, driven by both technical and conceptual advances, promises to fill in these gaps, as well as provide direct information about human diseases and vaccination responses. Work on human immunity has already provided important additional perspectives on basic immunology such as the importance of clonal deletion to self-tolerance, and while many challenges remain, it seems inevitable that "the human model" will continue to inform us about the immune system and even allow for the discovery of new mechanisms.

B cells in the balance: Offsetting self-reactivity avoidance with protection against foreign.

Antibodies are theoretically limitless in their diversity and specificity to foreign antigens; however they are constrained by the need to avoid binding to self. Germinal centers (GC) allow diversification and maturation of the antibody response towards the foreign antigen. While self-tolerance mechanisms controlling self-reactivity during B cell maturation are well recognized, the mechanisms by which GCs balance self-tolerance and foreign binding especially in the face of cross-reactivity between self and foreign, remain much less well defined. In this review we explore the extent to which GC self-tolerance restricts affinity maturation. We present studies suggesting that the outcome is situationally dependent, affected by affinity and avidity to self-antigen, and the extent to which self-binding and foreign-binding are interdependent. While auto-reactive GC B cells can mutate away from self while maturing towards the foreign antigen, if no mutational trajectories allow for self-reactive redemption, self-tolerance prevails and GC responses to the foreign pathogen are restricted, except when self-tolerance checkpoints are relaxed. Finally, we consider whether polyreactivity is subject to the same level of restriction in GC responses, especially if polyreactivity is linked to an increase in foreign protection, as occurs in certain broadly neutralizing antibodies. Overall, the outcomes for GC B cells that bind self-antigen can range from redemption, transient relaxation in self-tolerance or restriction of the antibody response to the foreign pathogen.