ADAR1 deficiency in regulatory T cells leads to MDA5 and PKR dependent systemic autoimmunity in mice
ADAR1 deficiency in regulatory T cells leads to MDA5 and PKR dependent systemic autoimmunity in mice
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Date of Embargo
15.04.2028Type of Scholarly Publication
DissertationDate of Exam
06.03.2026Date of Publication
02.04.2026Advisor
Kato, HirokiCo-Referee
Förster, IrmgardMetadata
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Abstract
Type I interferon (IFN-I) production, triggered by innate sensors upon recognition of viral nucleic acids, is essential for antiviral host defense. Mutations in proteins involved in nucleic acid metabolism, sensing and downstream signaling, cause rare monogenic diseases termed type I interferonopathies, which are characterized by chronic increased production of IFN-I and expression of IFN stimulated genes (ISGs), and a variety of inflammatory and autoimmune phenotypes. Gain-of-function (GOF) mutations in IFIH1, encoding the dsRNA sensor MDA5, and loss-of-function (LOF) mutations in ADAR1 (ADAR1), which by adenosine-to-inosine editing of dsRNA prevents their aberrant sensing by MDA5, are associated with the interferonopathy Aicardi–Goutières syndrome (AGS).
Previous findings showed that expression of constitutively active MDA5 in regulatory T cells (Tregs) – crucial in preventing autoimmunity, led to autoimmune phenotypes in mice. It was therefore of interest if ADAR1 deficiency in Tregs (Foxp3∆Adar1), leading to aberrant MDA5 activation, would also be detrimental. Indeed, Foxp3∆Adar1 mice, exhibited Treg depletion, leading to lethal autoimmunity and autoinflammation. The involvement of pathways downstream of ADAR1 in Foxp3∆Adar1 phenotypes, was investigated by genetic ablation of MAVS (the signaling adaptor of MDA5), PKR and ZBP1 – two other innate sensors and ISGs activated upon ADAR1 deficiency. MAVS knockout improved inflammatory phenotypes, but did not prevent Treg depletion. Moreover, in vivo inhibition of the IFN-I receptor (IFNAR) before phenotypic onset, prolonged Mavs−/−Foxp3ΔAdar1 survival, indicating enhanced IFNAR signaling independent of MDA5–MAVS. While ZBP1 knockout had minor effects, PKR knockout prevented Treg depletion – highlighting its involvement in Foxp3∆Adar1 phenotypes. Accordingly, MAVS and PKR double-knockout fully rescued Foxp3∆Adar1 mice.
Notably, patients with AGS carrying mutations in ADAR1 and IFIH1, exhibited reduced percentages of highly suppressive effector Tregs, markedly associated with ADAR1 LOF. While supported by evidence in mice, this finding is limited by human non-Tregs that inexplicably express the Treg-integral protein FOXP3. Nevertheless, it would be valuable to understand how Tregs are affected by interferonopathy-causing mutations, to examine their potential role in the pathogenesis of these diseases, and explore methods that enhance Treg function to ameliorate autoimmune symptoms.
Previous findings showed that expression of constitutively active MDA5 in regulatory T cells (Tregs) – crucial in preventing autoimmunity, led to autoimmune phenotypes in mice. It was therefore of interest if ADAR1 deficiency in Tregs (Foxp3∆Adar1), leading to aberrant MDA5 activation, would also be detrimental. Indeed, Foxp3∆Adar1 mice, exhibited Treg depletion, leading to lethal autoimmunity and autoinflammation. The involvement of pathways downstream of ADAR1 in Foxp3∆Adar1 phenotypes, was investigated by genetic ablation of MAVS (the signaling adaptor of MDA5), PKR and ZBP1 – two other innate sensors and ISGs activated upon ADAR1 deficiency. MAVS knockout improved inflammatory phenotypes, but did not prevent Treg depletion. Moreover, in vivo inhibition of the IFN-I receptor (IFNAR) before phenotypic onset, prolonged Mavs−/−Foxp3ΔAdar1 survival, indicating enhanced IFNAR signaling independent of MDA5–MAVS. While ZBP1 knockout had minor effects, PKR knockout prevented Treg depletion – highlighting its involvement in Foxp3∆Adar1 phenotypes. Accordingly, MAVS and PKR double-knockout fully rescued Foxp3∆Adar1 mice.
Notably, patients with AGS carrying mutations in ADAR1 and IFIH1, exhibited reduced percentages of highly suppressive effector Tregs, markedly associated with ADAR1 LOF. While supported by evidence in mice, this finding is limited by human non-Tregs that inexplicably express the Treg-integral protein FOXP3. Nevertheless, it would be valuable to understand how Tregs are affected by interferonopathy-causing mutations, to examine their potential role in the pathogenesis of these diseases, and explore methods that enhance Treg function to ameliorate autoimmune symptoms.
Classification (DDC)
570 Biowissenschaften, Biologie 610 Medizin, GesundheitLuca, Domnica: ADAR1 deficiency in regulatory T cells leads to MDA5 and PKR dependent systemic autoimmunity in mice. - Bonn, 2026. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-89285
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-89285
@phdthesis{handle:20.500.11811/14071,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-89285,
author = {{Domnica Luca}},
title = {ADAR1 deficiency in regulatory T cells leads to MDA5 and PKR dependent systemic autoimmunity in mice},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2026,
month = apr,
note = {Type I interferon (IFN-I) production, triggered by innate sensors upon recognition of viral nucleic acids, is essential for antiviral host defense. Mutations in proteins involved in nucleic acid metabolism, sensing and downstream signaling, cause rare monogenic diseases termed type I interferonopathies, which are characterized by chronic increased production of IFN-I and expression of IFN stimulated genes (ISGs), and a variety of inflammatory and autoimmune phenotypes. Gain-of-function (GOF) mutations in IFIH1, encoding the dsRNA sensor MDA5, and loss-of-function (LOF) mutations in ADAR1 (ADAR1), which by adenosine-to-inosine editing of dsRNA prevents their aberrant sensing by MDA5, are associated with the interferonopathy Aicardi–Goutières syndrome (AGS).
Previous findings showed that expression of constitutively active MDA5 in regulatory T cells (Tregs) – crucial in preventing autoimmunity, led to autoimmune phenotypes in mice. It was therefore of interest if ADAR1 deficiency in Tregs (Foxp3∆Adar1), leading to aberrant MDA5 activation, would also be detrimental. Indeed, Foxp3∆Adar1 mice, exhibited Treg depletion, leading to lethal autoimmunity and autoinflammation. The involvement of pathways downstream of ADAR1 in Foxp3∆Adar1 phenotypes, was investigated by genetic ablation of MAVS (the signaling adaptor of MDA5), PKR and ZBP1 – two other innate sensors and ISGs activated upon ADAR1 deficiency. MAVS knockout improved inflammatory phenotypes, but did not prevent Treg depletion. Moreover, in vivo inhibition of the IFN-I receptor (IFNAR) before phenotypic onset, prolonged Mavs−/−Foxp3ΔAdar1 survival, indicating enhanced IFNAR signaling independent of MDA5–MAVS. While ZBP1 knockout had minor effects, PKR knockout prevented Treg depletion – highlighting its involvement in Foxp3∆Adar1 phenotypes. Accordingly, MAVS and PKR double-knockout fully rescued Foxp3∆Adar1 mice.
Notably, patients with AGS carrying mutations in ADAR1 and IFIH1, exhibited reduced percentages of highly suppressive effector Tregs, markedly associated with ADAR1 LOF. While supported by evidence in mice, this finding is limited by human non-Tregs that inexplicably express the Treg-integral protein FOXP3. Nevertheless, it would be valuable to understand how Tregs are affected by interferonopathy-causing mutations, to examine their potential role in the pathogenesis of these diseases, and explore methods that enhance Treg function to ameliorate autoimmune symptoms.},
url = {https://hdl.handle.net/20.500.11811/14071}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-89285,
author = {{Domnica Luca}},
title = {ADAR1 deficiency in regulatory T cells leads to MDA5 and PKR dependent systemic autoimmunity in mice},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2026,
month = apr,
note = {Type I interferon (IFN-I) production, triggered by innate sensors upon recognition of viral nucleic acids, is essential for antiviral host defense. Mutations in proteins involved in nucleic acid metabolism, sensing and downstream signaling, cause rare monogenic diseases termed type I interferonopathies, which are characterized by chronic increased production of IFN-I and expression of IFN stimulated genes (ISGs), and a variety of inflammatory and autoimmune phenotypes. Gain-of-function (GOF) mutations in IFIH1, encoding the dsRNA sensor MDA5, and loss-of-function (LOF) mutations in ADAR1 (ADAR1), which by adenosine-to-inosine editing of dsRNA prevents their aberrant sensing by MDA5, are associated with the interferonopathy Aicardi–Goutières syndrome (AGS).
Previous findings showed that expression of constitutively active MDA5 in regulatory T cells (Tregs) – crucial in preventing autoimmunity, led to autoimmune phenotypes in mice. It was therefore of interest if ADAR1 deficiency in Tregs (Foxp3∆Adar1), leading to aberrant MDA5 activation, would also be detrimental. Indeed, Foxp3∆Adar1 mice, exhibited Treg depletion, leading to lethal autoimmunity and autoinflammation. The involvement of pathways downstream of ADAR1 in Foxp3∆Adar1 phenotypes, was investigated by genetic ablation of MAVS (the signaling adaptor of MDA5), PKR and ZBP1 – two other innate sensors and ISGs activated upon ADAR1 deficiency. MAVS knockout improved inflammatory phenotypes, but did not prevent Treg depletion. Moreover, in vivo inhibition of the IFN-I receptor (IFNAR) before phenotypic onset, prolonged Mavs−/−Foxp3ΔAdar1 survival, indicating enhanced IFNAR signaling independent of MDA5–MAVS. While ZBP1 knockout had minor effects, PKR knockout prevented Treg depletion – highlighting its involvement in Foxp3∆Adar1 phenotypes. Accordingly, MAVS and PKR double-knockout fully rescued Foxp3∆Adar1 mice.
Notably, patients with AGS carrying mutations in ADAR1 and IFIH1, exhibited reduced percentages of highly suppressive effector Tregs, markedly associated with ADAR1 LOF. While supported by evidence in mice, this finding is limited by human non-Tregs that inexplicably express the Treg-integral protein FOXP3. Nevertheless, it would be valuable to understand how Tregs are affected by interferonopathy-causing mutations, to examine their potential role in the pathogenesis of these diseases, and explore methods that enhance Treg function to ameliorate autoimmune symptoms.},
url = {https://hdl.handle.net/20.500.11811/14071}
}
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