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NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity

The NR4A family of orphan nuclear receptors (Nr4a1–3) plays redundant roles to establish and maintain Treg identity; deletion of multiple family members in the thymus results in Treg deficiency and a severe inflammatory disease. Consequently, it has been challenging to unmask redundant functions of...

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Autores principales: Hiwa, Ryosuke, Nielsen, Hailyn V., Mueller, James L., Mandla, Ravi, Zikherman, Julie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492309/
https://www.ncbi.nlm.nih.gov/pubmed/34343134
http://dx.doi.org/10.1172/jci.insight.151005
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author Hiwa, Ryosuke
Nielsen, Hailyn V.
Mueller, James L.
Mandla, Ravi
Zikherman, Julie
author_facet Hiwa, Ryosuke
Nielsen, Hailyn V.
Mueller, James L.
Mandla, Ravi
Zikherman, Julie
author_sort Hiwa, Ryosuke
collection PubMed
description The NR4A family of orphan nuclear receptors (Nr4a1–3) plays redundant roles to establish and maintain Treg identity; deletion of multiple family members in the thymus results in Treg deficiency and a severe inflammatory disease. Consequently, it has been challenging to unmask redundant functions of the NR4A family in other immune cells. Here we use a competitive bone marrow chimera strategy, coupled with conditional genetic tools, to rescue Treg homeostasis and unmask such functions. Unexpectedly, chimeras harboring Nr4a1(–/–) Nr4a3(–/–) (double-knockout, DKO) bone marrow developed autoantibodies and a systemic inflammatory disease despite a replete Treg compartment of largely WT origin. This disease differs qualitatively from that seen with Treg deficiency and is B cell extrinsic. Negative selection of DKO thymocytes is profoundly impaired in a cell-intrinsic manner. Consistent with escape of self-reactive T cells into the periphery, DKO T cells with functional, phenotypic, and transcriptional features of anergy accumulated in chimeric mice. Nevertheless, we observed upregulation of genes encoding inflammatory mediators in anergic DKO T cells, and DKO T cells exhibited enhanced capacity for IL-2 production. These studies reveal cell-intrinsic roles for the NR4A family in both central and peripheral T cell tolerance and demonstrate that each is essential to preserve immune homeostasis.
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spelling pubmed-84923092021-10-07 NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity Hiwa, Ryosuke Nielsen, Hailyn V. Mueller, James L. Mandla, Ravi Zikherman, Julie JCI Insight Research Article The NR4A family of orphan nuclear receptors (Nr4a1–3) plays redundant roles to establish and maintain Treg identity; deletion of multiple family members in the thymus results in Treg deficiency and a severe inflammatory disease. Consequently, it has been challenging to unmask redundant functions of the NR4A family in other immune cells. Here we use a competitive bone marrow chimera strategy, coupled with conditional genetic tools, to rescue Treg homeostasis and unmask such functions. Unexpectedly, chimeras harboring Nr4a1(–/–) Nr4a3(–/–) (double-knockout, DKO) bone marrow developed autoantibodies and a systemic inflammatory disease despite a replete Treg compartment of largely WT origin. This disease differs qualitatively from that seen with Treg deficiency and is B cell extrinsic. Negative selection of DKO thymocytes is profoundly impaired in a cell-intrinsic manner. Consistent with escape of self-reactive T cells into the periphery, DKO T cells with functional, phenotypic, and transcriptional features of anergy accumulated in chimeric mice. Nevertheless, we observed upregulation of genes encoding inflammatory mediators in anergic DKO T cells, and DKO T cells exhibited enhanced capacity for IL-2 production. These studies reveal cell-intrinsic roles for the NR4A family in both central and peripheral T cell tolerance and demonstrate that each is essential to preserve immune homeostasis. American Society for Clinical Investigation 2021-09-08 /pmc/articles/PMC8492309/ /pubmed/34343134 http://dx.doi.org/10.1172/jci.insight.151005 Text en © 2021 Hiwa et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Hiwa, Ryosuke
Nielsen, Hailyn V.
Mueller, James L.
Mandla, Ravi
Zikherman, Julie
NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity
title NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity
title_full NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity
title_fullStr NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity
title_full_unstemmed NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity
title_short NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity
title_sort nr4a family members regulate t cell tolerance to preserve immune homeostasis and suppress autoimmunity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492309/
https://www.ncbi.nlm.nih.gov/pubmed/34343134
http://dx.doi.org/10.1172/jci.insight.151005
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