Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver
The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model...
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doaj-562c142691284b8baadaf1974c991cea2021-08-03T00:11:05ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-03-0166Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liverMax PretiLena SchlottDavid LübberingDaria KrzikallaAnna-Lena MüllerFenja A. SchuranTobias PochMiriam SchakatSören WeidemannAnsgar W. LohseChristina Weiler-NormannMarcial SebodeDorothee SchwingeChristoph SchrammAntonella CarambiaJohannes HerkelThe liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II–restricted model peptide in hepatocytes by autoreactive CD4+ T cells. We found that the hepatic peptide was not expressed in the thymus, leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4+ T cells. In the liver, autoreactive CD4+ effector T cells accumulated within portal ectopic lymphoid structures and maturated toward pathogenic IFN-γ and TNF coproducing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs but not of nonspecific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation, and reduced expression of Foxp3. As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared with that of nonspecific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation.https://doi.org/10.1172/jci.insight.141462AutoimmunityHepatology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Max Preti Lena Schlott David Lübbering Daria Krzikalla Anna-Lena Müller Fenja A. Schuran Tobias Poch Miriam Schakat Sören Weidemann Ansgar W. Lohse Christina Weiler-Normann Marcial Sebode Dorothee Schwinge Christoph Schramm Antonella Carambia Johannes Herkel |
spellingShingle |
Max Preti Lena Schlott David Lübbering Daria Krzikalla Anna-Lena Müller Fenja A. Schuran Tobias Poch Miriam Schakat Sören Weidemann Ansgar W. Lohse Christina Weiler-Normann Marcial Sebode Dorothee Schwinge Christoph Schramm Antonella Carambia Johannes Herkel Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver JCI Insight Autoimmunity Hepatology |
author_facet |
Max Preti Lena Schlott David Lübbering Daria Krzikalla Anna-Lena Müller Fenja A. Schuran Tobias Poch Miriam Schakat Sören Weidemann Ansgar W. Lohse Christina Weiler-Normann Marcial Sebode Dorothee Schwinge Christoph Schramm Antonella Carambia Johannes Herkel |
author_sort |
Max Preti |
title |
Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver |
title_short |
Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver |
title_full |
Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver |
title_fullStr |
Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver |
title_full_unstemmed |
Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver |
title_sort |
failure of thymic deletion and instability of autoreactive tregs drive autoimmunity in immune-privileged liver |
publisher |
American Society for Clinical investigation |
series |
JCI Insight |
issn |
2379-3708 |
publishDate |
2021-03-01 |
description |
The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II–restricted model peptide in hepatocytes by autoreactive CD4+ T cells. We found that the hepatic peptide was not expressed in the thymus, leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4+ T cells. In the liver, autoreactive CD4+ effector T cells accumulated within portal ectopic lymphoid structures and maturated toward pathogenic IFN-γ and TNF coproducing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs but not of nonspecific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation, and reduced expression of Foxp3. As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared with that of nonspecific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation. |
topic |
Autoimmunity Hepatology |
url |
https://doi.org/10.1172/jci.insight.141462 |
work_keys_str_mv |
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