Hepatic T Cell Tolerance Induction in An Inflammatory Environment

2017 ◽  
Vol 36 (2) ◽  
pp. 156-166 ◽  
Author(s):  
Janine Dywicki ◽  
Fatih Noyan ◽  
Ana Clara Misslitz ◽  
Martin Hapke ◽  
Melanie Galla ◽  
...  
Keyword(s):  
T Cells ◽  
Tolerance Induction ◽  
T Cell Tolerance ◽  
Tolerance Mechanism ◽  
Autoreactive T Cells ◽  
Adenoviral Infection ◽  
Precursor Frequency ◽  
Self Antigen ◽  
Very High ◽  
Potential Tolerance

For the development of autoimmune hepatitis (AIH), genetic predisposition and environmental triggers are of major importance. Although experimental AIH can be induced in genetically susceptible mice, the low precursor frequency of autoreactive T cells hampers a deeper analysis of liver-specific T cells. Here, we established a system where the model antigen hemagglutinin (HA) is expressed exclusively in hepatocytes of Rosa26-HA mice following administration of a replication deficient adenovirus expressing Cre recombinase (Ad-Cre). Under these conditions, hepatocytes mimic the generation of altered-self neoantigens. To follow autoreactive T cells during AIH, we adoptively transferred HA-­specific Cl4-TCR and 6.5-TCR T cells into Ad-Cre infected ­Rosa26-HA mice. Alternatively, Rosa26-HA mice have been crossed with TCR transgenic mice that were infected with Ad-Cre to break hepatic tolerance and induce the expression of the HA antigen as a hepatic self-antigen. Surprisingly, neither adoptive transfer nor a very high precursor frequency of autoreactive T cells was able to break tolerance in the context of adenoviral infection. The low proliferation of the antigen experienced autoreactive T cells despite the presence of the autoantigen and inflammation points to anergy as a potential tolerance mechanism. This model underscores the crucial importance of genetic susceptibility to break tolerance against hepatic autoantigens.

scholarly journals Fas/FasL Signaling Regulates CD8 Expression During Exposure to Self-Antigens

2021 ◽  
Vol 12 ◽  
Author(s):  
Giovanna Flores-Mendoza ◽  
Noé Rodríguez-Rodríguez ◽  
Rosa M. Rubio ◽  
Iris K. Madera-Salcedo ◽  
Florencia Rosetti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Peripheral Tolerance ◽  
Tolerance Mechanism ◽  
Genetic Deficiency ◽  
Self Antigen ◽  
Insight Into ◽  
Self Antigens

Activation of self-reactive CD8+ T cells induces a peripheral tolerance mechanism that involves loss of CD8 expression. Because genetic deficiency of Fas and Fasl causes the accumulation of double-negative (DN; CD3+ TCR-αβ+ CD4- CD8-) T cells that have been proposed to derive from CD8+ cells, we decided to explore the role of Fas and FasL in self-antigen-induced CD8 downregulation. To this end, we quantified Fas and FasL induction by different stimuli and analyzed the effects of Fas/FasL deficiency during a protective immune response and after exposure to self-antigens. Our data describes how Fas and FasL upregulation differs depending on the setting of CD8 T cell activation and demonstrates that Fas/FasL signaling maintains CD8 expression during repetitive antigen stimulation and following self-antigen encounter. Together, our results reveal an unexpected role of Fas/FasL signaling and offer a new insight into the role of these molecules in the regulation of immune tolerance.

scholarly journals Monocytes prime autoreactive T cells after myocardial infarction

2020 ◽  
Vol 318 (1) ◽  
pp. H116-H123 ◽  
Author(s):  
Matthew DeBerge ◽  
Shuangjin Yu ◽  
Shirley Dehn ◽  
Igal Ifergan ◽  
Xin Yi Yeap ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
T Cells ◽  
Lymph Node ◽  
Therapeutic Targeting ◽  
Autoreactive T Cells ◽  
Inflammatory Monocytes ◽  
Monocyte Recruitment ◽  
Antigen Trafficking ◽  
Self Antigen ◽  
Mhc Antigen

In humans, loss of central tolerance for the cardiac self-antigen α-myosin heavy chain (α-MHC) leads to circulation of cardiac autoreactive T cells and renders the heart susceptible to autoimmune attack after acute myocardial infarction (MI). MI triggers profound tissue damage, releasing danger signals and self-antigen by necrotic cardiomyocytes, which lead to recruitment of inflammatory monocytes. We hypothesized that excessive inflammation by monocytes contributes to the initiation of adaptive immune responses to cardiac self-antigen. Using an experimental model of MI in α-MHC-mCherry reporter mice, which specifically express mCherry in cardiomyocytes, we detected α-MHC antigen in myeloid cells in the heart-draining mediastinal lymph node (MLN) 7 days after MI. To test whether monocytes were required for cardiac self-antigen trafficking to the MLN, we blocked monocyte recruitment with a C-C motif chemokine receptor type 2 (CCR2) antagonist or immune modifying nanoparticles (IMP). Blockade of monocyte recruitment reduced α-MHC antigen detection in the MLN after MI. Intramyocardial injection of the model antigen ovalbumin into OT-II transgenic mice demonstrated the requirement for monocytes in antigen trafficking and T-cell activation in the MLN. Finally, in nonobese diabetic mice, which are prone to postinfarction autoimmunity, blockade of monocyte recruitment reduced α-MHC-specific responses leading to improved tissue repair and ventricular function 28 days after MI. Taken together, these data support a role for monocytes in the onset of pathological cardiac autoimmunity following MI and suggest that therapeutic targeting of monocytes may mitigate postinfarction autoimmunity in humans. NEW & NOTEWORTHY Our study newly identifies a role for inflammatory monocytes in priming an autoimmune T-cell response after myocardial infarction. Select inhibition of monocyte recruitment to the infarct prevents trafficking of cardiac self-antigen and activation of cardiac myosin reactive T cells in the heart-draining lymph node. Therapeutic targeting of inflammatory monocytes may limit autoimmune responses to improve cardiac remodeling and preserve left ventricular function after myocardial infarction.

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.

Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3964-3969 ◽  
Author(s):  
Ping Lan ◽  
Lan Wang ◽  
Bintou Diouf ◽  
Hiroshi Eguchi ◽  
Hui Su ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tolerance Induction ◽  
Skin Grafting ◽  
Mixed Chimerism ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Human T Cell ◽  
Human T Cells ◽  
Hematopoietic Chimerism

Abstract Xenotransplantation from pigs could provide a potential solution to the severe shortage of allogeneic donor organs. Because xenogeneic tissues are subject to vigorous immune rejection, tolerance induction is likely to be essential to the success of clinical xenotransplantation. Here we explore the possibility of inducing human T-cell tolerance to porcine xenografts through mixed chimerism. We previously showed that NOD/SCID-Tg mice expressing porcine cytokine transgenes permit the induction of durable porcine hematopoietic chimerism. In this study we achieved human T-cell development in these mice by engrafting human fetal thymus/liver tissues. In porcine hematopoietic chimeras, human thymus grafts were populated with porcine class IIhigh cells in addition to human cells, and human T cells were tolerant of the porcine hematopoietic donor as measured by mixed lymphocyte reaction assay and skin grafting. This study proves the principle that porcine chimerism induces tolerance of xenoreactive human T cells.

scholarly journals Strong T cell tolerance in parent----F1 bone marrow chimeras prepared with supralethal irradiation. Evidence for clonal deletion and anergy.

1990 ◽  
Vol 171 (4) ◽  
pp. 1101-1121 ◽  
Author(s):  
E K Gao ◽  
D Lo ◽  
J Sprent
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Tolerance Induction ◽  
Thymic Epithelial Cells ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Cd4 Cells ◽  
Clonal Deletion ◽  
Host Type

T cell tolerance induction was examined in long-term H-2-heterozygous parent----F1 chimeras prepared with supralethal irradiation (1,300 rad). Although these chimeras appeared to be devoid of host-type APC, the donor T cells developing in the chimeras showed marked tolerance to host-type H-2 determinants. Tolerance to the host appeared to be virtually complete in four assay systems: (a) primary mixed lymphocyte reactions (MLR) of purified lymph node (LN) CD8+ cells (+/- IL-2); (b) primary MLR of CD4+ (CD8-) thymocytes; (c) skin graft rejection; and (d) induction of lethal graft-vs.-host disease by CD4+ cells. Similar tolerance was observed in chimeras given double irradiation. The only assay in which the chimera T cells failed to show near-total tolerance to the host was the primary MLR of post-thymic CD4+ cells. In this assay, LN CD4+ cells regularly gave a significant antihost MLR. The magnitude of this response was two- to fourfold less than the response of normal parental strain CD4+ cells and, in I-E(-)----I-E+ chimeras, was paralleled by approximately 70% deletion of V beta 11+ cells. Since marked tolerance was evident at the level of mature thymocytes, tolerance induction in the chimeras presumably occurred in the thymus itself. The failure to detect host APC in the thymus implies that tolerance reflected contact with thymic epithelial cells (and/or other non-BM-derived cells in the thymus). To account for the residual host reactivity of LN CD4+ cells and the incomplete deletion of V beta 11+ cells, it is suggested that T cell contact with thymic epithelial cells induced clonal deletion of most of the host-reactive T cells but spared a proportion of these cells (possibly low affinity cells). Since these latter cells appeared to be functionally inert in the thymus (in contrast to LN), we suggest that the thymic epithelial cells induced a temporary form of anergy in the remaining host-reactive thymocytes. This anergic state disappeared when the T cells left the thymus and reached LN.

scholarly journals Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance.

1995 ◽  
Vol 181 (3) ◽  
pp. 993-1003 ◽  
Author(s):  
B Rocha ◽  
A Grandien ◽  
A A Freitas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tolerance Induction ◽  
Cell Receptor ◽  
T Cell Tolerance ◽  
Effector Functions ◽  
Antigen Persistence ◽  
Alpha Beta ◽  
Male Specific

We studied the interactions of male-specific T cell receptor (TCR)-alpha/beta-transgenic (TG) cells with different concentrations of male antigen in vivo. We constructed mouse chimeras expressing different amounts of male antigen by injecting thymectomized, lethally irradiated mice with various ratios of male (immunoglobulin [Ig] Ha) and female (IgHb) bone marrow. These chimeras were injected with male-specific TCR-alpha/beta-trangenic cells. These experiments allowed us to monitor antigen persistence and characterize antigen-specific T cells in terms of their frequency, reactivity, and effector functions (as tested by elimination of male B cells in vivo). In the absence of antigen, virgin TG cells persisted but did not expand. Transient exposure to antigen resulted in cell expansion, followed by the persistence of increased numbers of antigen-reactive T cells. In contrast, antigen persistence was followed by two independent mechanisms of tolerance induction: anergy (at high antigen concentrations), where T cells did not differentiate into effector functions but persisted in vivo as unresponsive T cells, and exhaustion (at lower antigen concentrations), where differentiation into effector functions (B cell elimination) occurred but was followed by the disappearance of antigen-specific T cells.

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.

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