scholarly journals Thymic Self-Antigen Expression for the Design of a Negative/Tolerogenic Self-Vaccine against Type 1 Diabetes

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Aziz Alami Chentoufi ◽  
Vincent Geenen
Keyword(s):  
T Cells ◽  
Antigen Expression ◽  
Immunological Tolerance ◽  
Fetal Life ◽  
Cross Tolerance ◽  
Self Tolerance ◽  
Organ Specific ◽  
Dominant Member ◽  
Prevention And Cure ◽  
Self Antigen

Before being able to react against infectious non-self-antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins, and this critical process essentially takes place in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programming central self-tolerance to pancreatic insulin-secreting isletβcells, leading to the breakdown of immune homeostasis with an enrichment of isletβcell reactive effector T cells and a deficiency ofβcell-specific natural regulatory T cells (nTreg) in the peripheral T-lymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. Based on the close homology and cross-tolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called “negative/tolerogenic self-vaccination”, is currently developed for prevention and cure of T1D. If this approach were found to be effective for reprogramming immunological tolerance in T1D, it could pave the way for the design of negative self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases.

scholarly journals Peripheral Deletion of Autoreactive CD8 T Cells by Cross Presentation of Self-Antigen Occurs by a Bcl-2–inhibitable Pathway Mediated by Bim

2002 ◽  
Vol 196 (7) ◽  
pp. 947-955 ◽  
Author(s):  
Gayle M. Davey ◽  
Christian Kurts ◽  
Jacques F.A.P. Miller ◽  
Philippe Bouillet ◽  
Andreas Strasser ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Presentation Of Self ◽  
Cross Tolerance ◽  
Transgenic Expression ◽  
Cross Presentation ◽  
Self Tolerance ◽  
Initial Activation ◽  
Self Antigen

By transgenic expression of ovalbumin (OVA) as a model self antigen in the β cells of the pancreas, we have shown that self tolerance can be maintained by the cross-presentation of this antigen on dendritic cells in the draining lymph nodes. Such cross-presentation causes initial activation of OVA-specific CD8 T cells, which proliferate but are ultimately deleted; a process referred to as cross-tolerance. Here, we investigated the molecular basis of cross-tolerance. Deletion of CD8 T cells was prevented by overexpression of Bcl-2, indicating that cross-tolerance was mediated by a Bcl-2 inhibitable pathway. Recently, Bim, a pro-apoptotic Bcl-2 family member whose function can be inhibited by Bcl-2, was found to play a critical role in the deletion of autoreactive thymocytes, leading us to examine its role in cross-tolerance. Bim-deficient T cells were not deleted in response to cross-presented self-antigen, strongly implicating Bim as the pro-apoptotic mediator of cross-tolerance.

scholarly journals Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 984-991 ◽  
Author(s):  
Sara Morlacchi ◽  
Cristiana Soldani ◽  
Antonella Viola ◽  
Adelaida Sarukhan
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Expression ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Clonal Deletion ◽  
Thymic Epithelium ◽  
Self Antigen ◽  
Self Antigens

Abstract Multiple mechanisms operate to ensure T-cell tolerance toward self-antigens. Three main processes have been described: clonal deletion, anergy, and deviation to CD4+ regulatory T cells (Tregs) that suppress autoreactive T cells that have escaped the first 2 mechanisms. Although it is accepted that dendritic cells (DCs) and B cells contribute in maintaining T-cell tolerance to self-antigens, their relative contribution and the processes involved under physiologic conditions remain only partially characterized. In this study, we used different transgenic mouse models to obtain chimeras where a neo self-antigen is expressed by thymic epithelium and/or by DCs or B cells. We found that expression of cognate ligand in the thymus enhances antigen-specific FoxP3+ cells independently of whether the self-antigen is expressed on thymic epithelium or only on DCs, but not on B cells. On the contrary, self-antigen expression by B cells was very efficient in inducing FoxP3+ cells in the periphery, whereas self-antigen expression by DC led mainly to deletion and anergy of antigen-specific FoxP3− cells. The results presented in this study underline the role of B cells in Treg induction and may have important implications in clinical protocols aimed at the peripheral expansion of Tregs in patients.

scholarly journals Thymus Dysfunction in the Development of Type 1 Diabetes and Endocrine Autoimmune Diseases

2009 ◽  
Vol 05 (0) ◽  
pp. 24
Author(s):  
Vincent Geenen ◽  
Olivier Dardenne ◽  
◽  
Keyword(s):  
Type 1 Diabetes ◽  
Autoimmune Diseases ◽  
Autoimmune Response ◽  
Thymic Epithelial Cells ◽  
Self Tolerance ◽  
Genes Encoding ◽  
Organ Specific ◽  
Dominant Member ◽  
Large Repertoire

The discovery that thymic epithelium from many species expresses a large repertoire of genes encoding neuroendocrine and other tissuerestricted antigens has radically changed our knowledge of the pathogenic mechanisms underlying the development of organ-specific autoimmune diseases such as type 1 diabetes and autoimmune endocrine diseases. Rather than a breakdown of immunological selftolerance in periphery, there is mounting evidence that the diabetogenic autoimmune response may first arise from a thymus dysfunction in the central programming of β-cell self-tolerance. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin gene/protein family expressed in thymic epithelial cells (TECs) from different species, and Igf2-/- mice fail to programme complete tolerance to insulin. Based on the homology between insulin, the primary and immunogenic auto-antigen of type 1 diabetes, and IGF-2, the tolerogenic selfantigen of the insulin family, the design of a regulatory/negative self-vaccination for prevention against type 1 diabetes has been proposed and is under development.

scholarly journals Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD

Blood ◽  
2015 ◽  
Vol 125 (17) ◽  
pp. 2720-2723 ◽  
Author(s):  
Simone Dertschnig ◽  
Mathias M. Hauri-Hohl ◽  
Madeleine Vollmer ◽  
Georg A. Holländer ◽  
Werner Krenger
Keyword(s):  
T Cells ◽  
Functional Impairment ◽  
Cd4 T Cells ◽  
Acute Gvhd ◽  
De Novo ◽  
Antigen Expression ◽  
Autoreactive T Cells ◽  
Key Points ◽  
Self Antigen

Key Points Loss of thymic ectopic self-antigen expression during murine acute GVHD is responsible for the de novo generation of autoreactive T cells. Functional impairment of the thymus medulla mechanistically links acute GVHD to posttransplantation autoimmunity.

scholarly journals Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity

2009 ◽  
Vol 206 (3) ◽  
pp. 549-559 ◽  
Author(s):  
Caspar Ohnmacht ◽  
Andrea Pullner ◽  
Susan B.S. King ◽  
Ingo Drexler ◽  
Stefanie Meier ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Steady State ◽  
Cd4 T Cells ◽  
Tolerance Induction ◽  
Immunological Tolerance ◽  
Peripheral Tissues ◽  
Reduced Body ◽  
Self Tolerance ◽  
Single Positive

Lack of immunological tolerance against self-antigens results in autoimmune disorders. During onset of autoimmunity, dendritic cells (DCs) are thought to be critical for priming of self-reactive T cells that have escaped tolerance induction. However, because DCs can also induce T cell tolerance, it remains unclear whether DCs are required under steady-state conditions to prevent autoimmunity. To address this question, we crossed CD11c-Cre mice with mice that express diphtheria toxin A (DTA) under the control of a loxP-flanked neomycin resistance (neoR) cassette from the ROSA26 locus. Cre-mediated removal of the neoR cassette leads to DTA expression and constitutive loss of conventional DCs, plasmacytoid DCs, and Langerhans cells. These DC-depleted (ΔDC) mice showed increased frequencies of CD4 single-positive thymocytes and infiltration of CD4 T cells into peripheral tissues. They developed spontaneous autoimmunity characterized by reduced body weight, splenomegaly, autoantibody formation, neutrophilia, high numbers of Th1 and Th17 cells, and inflammatory bowel disease. Pathology could be induced by reconstitution of wild-type (WT) mice with bone marrow (BM) from ΔDC mice, whereas mixed BM chimeras that received BM from ΔDC and WT mice remained healthy. This demonstrates that DCs play an essential role to protect against fatal autoimmunity under steady-state conditions.

Induction of self-tolerance in T cells but not B cells of transgenic mice expressing little self antigen

Science ◽  
1991 ◽  
Vol 251 (4998) ◽  
pp. 1223-1225 ◽  
Author(s):  
S Adelstein ◽  
H Pritchard-Briscoe ◽  
T. Anderson ◽  
J Crosbie ◽  
G Gammon ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Transgenic Mice ◽  
Self Tolerance ◽  
Self Antigen

scholarly journals Coxsackievirus B4 Transplacental Infection Severely Disturbs Central Tolerogenic Mechanisms in the Fetal Thymus

2021 ◽  
Vol 9 (7) ◽  
pp. 1537
Author(s):  
Aymen Halouani ◽  
Hélène Michaux ◽  
Habib Jmii ◽  
Charlotte Trussart ◽  
Ahlem Chahbi ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Level ◽  
In Utero ◽  
Thymic Epithelial Cells ◽  
Fetal Life ◽  
Central Tolerance ◽  
Coxsackievirus B4 ◽  
Self Tolerance ◽  
Coxsackievirus B ◽  
Transplacental Infection

Thymus plays a fundamental role in central tolerance establishment, especially during fetal life, through the generation of self-tolerant T cells. This process consists in T cells education by presenting them tissue-restricted autoantigens promiscuously expressed by thymic epithelial cells (TECs), thus preventing autoimmunity. Thymus infection by Coxsackievirus B (CV-B) during fetal life is supposed to disturb thymic functions and, hence, to be an inducing or accelerating factor in the genesis of autoimmunity. To further investigate this hypothesis, in our current study, we analyzed thymic expression of autoantigens, at the transcriptional and protein level, following in utero infection by CV-B4. mRNA expression levels of Igf2 and Myo7, major autoantigens of pancreas and heart, respectively, were analyzed in whole thymus and in enriched TECs together along with both transcription factors, Aire and Fezf2, involved in autoantigens expression in the thymus. Results show that in utero infection by CV-B4 induces a significant decrease in Igf2 and Myo7 expression at both mRNA and protein level in whole thymus and in enriched TECs as well. Moreover, a correlation between viral load and autoantigens expression can be observed in the whole thymus, indicating a direct effect of in utero infection by CV-B4 on autoantigens expression. Together, these results indicate that an in utero infection of the thymus by CV-B4 may interfere with self-tolerance establishment in TECs by decreasing autoantigen expression at both mRNA and protein level and thereby increase the risk of autoimmunity onset.

scholarly journals Avidity maturation of memory CD8 T cells is limited by self-antigen expression

2008 ◽  
Vol 205 (8) ◽  
pp. 1859-1868 ◽  
Author(s):  
Michael J. Turner ◽  
Evan R. Jellison ◽  
Elizabeth G. Lingenheld ◽  
Lynn Puddington ◽  
Leo Lefrançois
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Secondary Infection ◽  
Antigen Expression ◽  
Memory Cells ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Self Antigen ◽  
Avidity Maturation

Immune tolerance to self-antigens is a complex process that utilizes multiple mechanisms working in concert to maintain homeostasis and prevent autoimmunity. We developed a system that revealed a population of self-specific CD8 T cells within the endogenous T cell repertoire. Immunization of ovalbumin (OVA)-expressing transgenic mice with recombinant viruses expressing OVA-peptide variants induced self-reactive T cells in vivo that matured into memory T cells able to respond to secondary infection. However, whereas the avidity of memory cells in normal mice increased dramatically with repeated immunizations, avidity maturation was limited for self-specific CD8 T cells. Despite decreased avidity, such memory cells afforded protection against infection, but did not induce overt autoimmunity. Further, up-regulation of self-antigen expression in dendritic cells using an inducible system promoted programmed death-1 expression, but not clonal expansion of preexisting memory cells. Thus, the self-reactive T cell repertoire is controlled by overlapping mechanisms influenced by antigen dose.

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