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T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice

IL-2Rα, in part, comprises the high affinity receptor for IL-2, a cytokine important in immune proliferation, activation, and regulation. IL-2Rα deficient mice (IL-2Rα-KO) develop systemic autoimmune disease and die from severe anemia between 18 and 80 days of age. These mice develop kinetically dis...

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Autores principales: Mullins, Genevieve N., Valentine, Kristen M., Al-Kuhlani, Mufadhal, Davini, Dan, Jensen, Kirk D. C., Hoyer, Katrina K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738527/
https://www.ncbi.nlm.nih.gov/pubmed/33319815
http://dx.doi.org/10.1038/s41598-020-78975-y
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author Mullins, Genevieve N.
Valentine, Kristen M.
Al-Kuhlani, Mufadhal
Davini, Dan
Jensen, Kirk D. C.
Hoyer, Katrina K.
author_facet Mullins, Genevieve N.
Valentine, Kristen M.
Al-Kuhlani, Mufadhal
Davini, Dan
Jensen, Kirk D. C.
Hoyer, Katrina K.
author_sort Mullins, Genevieve N.
collection PubMed
description IL-2Rα, in part, comprises the high affinity receptor for IL-2, a cytokine important in immune proliferation, activation, and regulation. IL-2Rα deficient mice (IL-2Rα-KO) develop systemic autoimmune disease and die from severe anemia between 18 and 80 days of age. These mice develop kinetically distinct autoimmune progression, with approximately a quarter dying by 21 days of age and half dying after 30 days. This research aims to define immune parameters and cytokine signaling that distinguish cohorts of IL-2Rα-KO mice that develop early- versus late-stage autoimmune disease. To investigate these differences, we evaluated complete blood counts (CBC), antibody binding of RBCs, T cell numbers and activation, hematopoietic progenitor changes, and signaling kinetics, during autoimmune hemolytic anemia (AIHA) and bone marrow failure. We identified several alterations that, when combined, correlate to disease kinetics. Early onset disease correlates with anti-RBC antibodies, lower hematocrit, and reduced IL-7 signaling. CD8 regulatory T cells (Tregs) have enhanced apoptosis in early disease. Further, early and late end stage disease, while largely similar, had several differences suggesting distinct mechanisms drive autoimmune disease kinetics. Therefore, IL-2Rα-KO disease pathology rates, driven by T cell signaling, promote effector T cell activation and expansion and Treg dysfunction.
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spelling pubmed-77385272020-12-17 T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice Mullins, Genevieve N. Valentine, Kristen M. Al-Kuhlani, Mufadhal Davini, Dan Jensen, Kirk D. C. Hoyer, Katrina K. Sci Rep Article IL-2Rα, in part, comprises the high affinity receptor for IL-2, a cytokine important in immune proliferation, activation, and regulation. IL-2Rα deficient mice (IL-2Rα-KO) develop systemic autoimmune disease and die from severe anemia between 18 and 80 days of age. These mice develop kinetically distinct autoimmune progression, with approximately a quarter dying by 21 days of age and half dying after 30 days. This research aims to define immune parameters and cytokine signaling that distinguish cohorts of IL-2Rα-KO mice that develop early- versus late-stage autoimmune disease. To investigate these differences, we evaluated complete blood counts (CBC), antibody binding of RBCs, T cell numbers and activation, hematopoietic progenitor changes, and signaling kinetics, during autoimmune hemolytic anemia (AIHA) and bone marrow failure. We identified several alterations that, when combined, correlate to disease kinetics. Early onset disease correlates with anti-RBC antibodies, lower hematocrit, and reduced IL-7 signaling. CD8 regulatory T cells (Tregs) have enhanced apoptosis in early disease. Further, early and late end stage disease, while largely similar, had several differences suggesting distinct mechanisms drive autoimmune disease kinetics. Therefore, IL-2Rα-KO disease pathology rates, driven by T cell signaling, promote effector T cell activation and expansion and Treg dysfunction. Nature Publishing Group UK 2020-12-15 /pmc/articles/PMC7738527/ /pubmed/33319815 http://dx.doi.org/10.1038/s41598-020-78975-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mullins, Genevieve N.
Valentine, Kristen M.
Al-Kuhlani, Mufadhal
Davini, Dan
Jensen, Kirk D. C.
Hoyer, Katrina K.
T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice
title T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice
title_full T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice
title_fullStr T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice
title_full_unstemmed T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice
title_short T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice
title_sort t cell signaling and treg dysfunction correlate to disease kinetics in il-2rα-ko autoimmune mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738527/
https://www.ncbi.nlm.nih.gov/pubmed/33319815
http://dx.doi.org/10.1038/s41598-020-78975-y
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