Single-Cell RNA Sequencing Reveals Expanded Clones of Islet Antigen-Reactive CD4 + T Cells in Peripheral Blood of Subjects with Type 1 Diabetes

The significance of islet Ag-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects is unclear, partly because similar cells are also found in healthy control (HC) subjects. We hypothesized that key disease-associated cells would show evidence of prior Ag exposure, inferred fro...

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Veröffentlicht in:The Journal of immunology (1950) Jg. 199; H. 1; S. 323
Hauptverfasser: Cerosaletti, Karen, Barahmand-Pour-Whitman, Fariba, Yang, Junbao, DeBerg, Hannah A, Dufort, Matthew J, Murray, Sara A, Israelsson, Elisabeth, Speake, Cate, Gersuk, Vivian H, Eddy, James A, Reijonen, Helena, Greenbaum, Carla J, Kwok, William W, Wambre, Erik, Prlic, Martin, Gottardo, Raphael, Nepom, Gerald T, Linsley, Peter S
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.07.2017
Schlagworte:
Adult
CD4-Positive T-Lymphocytes - immunology
Clone Cells
Diabetes Mellitus, Type 1 - blood
Diabetes Mellitus, Type 1 - immunology
Female
Gene Expression Profiling
Humans
Immunologic Memory
Islets of Langerhans - immunology
Lymphocyte Activation
Male
Peptides - immunology
Phenotype
Receptors, Antigen, T-Cell, alpha-beta - immunology
Sequence Analysis, RNA
Single-Cell Analysis
ISSN:1550-6606, 1550-6606
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Zusammenfassung:The significance of islet Ag-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects is unclear, partly because similar cells are also found in healthy control (HC) subjects. We hypothesized that key disease-associated cells would show evidence of prior Ag exposure, inferred from expanded TCR clonotypes, and essential phenotypic properties in their transcriptomes. To test this, we developed single-cell RNA sequencing procedures for identifying TCR clonotypes and transcript phenotypes in individual T cells. We applied these procedures to analysis of islet Ag-reactive CD4 memory T cells from the blood of T1D and HC individuals after activation with pooled immunodominant islet peptides. We found extensive TCR clonotype sharing in Ag-activated cells, especially from individual T1D subjects, consistent with in vivo T cell expansion during disease progression. The expanded clonotype from one T1D subject was detected at repeat visits spanning >15 mo, demonstrating clonotype stability. Notably, we found no clonotype sharing between subjects, indicating a predominance of "private" TCR specificities. Expanded clones from two T1D subjects recognized distinct IGRP peptides, implicating this molecule as a trigger for CD4 T cell expansion. Although overall transcript profiles of cells from HC and T1D subjects were similar, profiles from the most expanded clones were distinctive. Our findings demonstrate that islet Ag-reactive CD4 memory T cells with unique Ag specificities and phenotypes are expanded during disease progression and can be detected by single-cell analysis of peripheral blood.
Bibliographie:ObjectType-Article-1
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ISSN:1550-6606
1550-6606
DOI:10.4049/jimmunol.1700172