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Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage

Type 1 diabetes (T1D) is an autoimmune disorder defined by CD8 T cell–mediated destruction of pancreatic β cells. We have previously shown that diabetogenic CD8 T cells in the islets of non-obese diabetic mice are phenotypically heterogeneous, but clonal heterogeneity remains relatively unexplored....

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Autores principales: Kasmani, Moujtaba Y, Ciecko, Ashley E, Brown, Ashley K, Petrova, Galina, Gorski, Jack, Chen, Yi-Guang, Cui, Weiguo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170949/
https://www.ncbi.nlm.nih.gov/pubmed/35667687
http://dx.doi.org/10.26508/lsa.202201503
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author Kasmani, Moujtaba Y
Ciecko, Ashley E
Brown, Ashley K
Petrova, Galina
Gorski, Jack
Chen, Yi-Guang
Cui, Weiguo
author_facet Kasmani, Moujtaba Y
Ciecko, Ashley E
Brown, Ashley K
Petrova, Galina
Gorski, Jack
Chen, Yi-Guang
Cui, Weiguo
author_sort Kasmani, Moujtaba Y
collection PubMed
description Type 1 diabetes (T1D) is an autoimmune disorder defined by CD8 T cell–mediated destruction of pancreatic β cells. We have previously shown that diabetogenic CD8 T cells in the islets of non-obese diabetic mice are phenotypically heterogeneous, but clonal heterogeneity remains relatively unexplored. Here, we use paired single-cell RNA and T-cell receptor sequencing (scRNA-seq and scTCR-seq) to characterize autoreactive CD8 T cells from the islets and spleens of non-obese diabetic mice. scTCR-seq demonstrates that CD8 T cells targeting the immunodominant β-cell epitope IGRP(206-214) exhibit restricted TCR gene usage. scRNA-seq identifies six clusters of autoreactive CD8 T cells in the islets and six in the spleen, including memory and exhausted cells. Clonal overlap between IGRP(206-214)–reactive CD8 T cells in the islets and spleen suggests these cells may circulate between the islets and periphery. Finally, we identify correlations between TCR genes and T-cell clonal expansion and effector fate. Collectively, our work demonstrates that IGRP(206-214)–specific CD8 T cells are phenotypically heterogeneous but clonally restricted, raising the possibility of selectively targeting these TCR structures for therapeutic benefit.
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spelling pubmed-91709492022-06-29 Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage Kasmani, Moujtaba Y Ciecko, Ashley E Brown, Ashley K Petrova, Galina Gorski, Jack Chen, Yi-Guang Cui, Weiguo Life Sci Alliance Research Articles Type 1 diabetes (T1D) is an autoimmune disorder defined by CD8 T cell–mediated destruction of pancreatic β cells. We have previously shown that diabetogenic CD8 T cells in the islets of non-obese diabetic mice are phenotypically heterogeneous, but clonal heterogeneity remains relatively unexplored. Here, we use paired single-cell RNA and T-cell receptor sequencing (scRNA-seq and scTCR-seq) to characterize autoreactive CD8 T cells from the islets and spleens of non-obese diabetic mice. scTCR-seq demonstrates that CD8 T cells targeting the immunodominant β-cell epitope IGRP(206-214) exhibit restricted TCR gene usage. scRNA-seq identifies six clusters of autoreactive CD8 T cells in the islets and six in the spleen, including memory and exhausted cells. Clonal overlap between IGRP(206-214)–reactive CD8 T cells in the islets and spleen suggests these cells may circulate between the islets and periphery. Finally, we identify correlations between TCR genes and T-cell clonal expansion and effector fate. Collectively, our work demonstrates that IGRP(206-214)–specific CD8 T cells are phenotypically heterogeneous but clonally restricted, raising the possibility of selectively targeting these TCR structures for therapeutic benefit. Life Science Alliance LLC 2022-06-06 /pmc/articles/PMC9170949/ /pubmed/35667687 http://dx.doi.org/10.26508/lsa.202201503 Text en © 2022 Kasmani et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Kasmani, Moujtaba Y
Ciecko, Ashley E
Brown, Ashley K
Petrova, Galina
Gorski, Jack
Chen, Yi-Guang
Cui, Weiguo
Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage
title Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage
title_full Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage
title_fullStr Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage
title_full_unstemmed Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage
title_short Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage
title_sort autoreactive cd8 t cells in nod mice exhibit phenotypic heterogeneity but restricted tcr gene usage
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170949/
https://www.ncbi.nlm.nih.gov/pubmed/35667687
http://dx.doi.org/10.26508/lsa.202201503
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