T cell self-reactivity during thymic development dictates the timing of positive selection

Abstract
Data availability
Article and author information
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Abstract

Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced TCR sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity down-regulate TCR sensitivity more slowly during positive selection, and associate membrane ion channel expression with thymocyte self-reactivity and progress through positive selection.

Data availability

RNA-seq data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE164896.

The following data sets were generated

1. Lutes LK
2. Steier Z
3. McIntyre LL
4. Pandey S
5. Kaminski J
6. Hoover AR
7. Ariotti S
8. Streets A
9. Yosef N
10. Robey EA
(2021) T cell self-reactivity during thymic development dictates the timing of positive selection
NCBI Gene Expression Omnibus, GSE164896.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE164896

The following previously published data sets were used

1. Jameson SC
2. Fulton RB
(2014) Comparison of mouse naïve (CD44lo) CD8+ T cells sorted into the highest and lowest 20% with respect to CD5
NCBI Gene Expression Omnibus, GSE62142.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE62142
1. Matson CA
2. Choi S
3. Zhao B
4. Ferenc L
5. Mitra AK
6. Love PE
7. Singh NJ
(2020) CD5 dynamically calibrates basal NF-KB signaling in T cells during thymic development and peripheral activation
NCBI Gene Expression Omnibus, GSE151395.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151395
(2009) ImmGen Microarray Phase 1
NCBI Gene Expression Omnibus, GSE15907.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15907

Article and author information

Author details

Lydia K Lutes

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Zoë Steier

Department of Bioengineering, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Laura L McIntyre

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Shraddha Pandey

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
James Kaminski

Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Ashley R Hoover

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Silvia Ariotti

Instituto de Medicina Molecular João Lobo Antunes, University of Lisbon, Lisbon, Portugal

Competing interests
The authors declare that no competing interests exist.
Aaron Streets

Department of Bioengineering, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Nir Yosef

Department of Electrical Engineering and Computer Science and the Center for Computational Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9004-1225
Ellen A Robey

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

For correspondence
erobey@berkeley.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3630-5266

Funding

National Institutes of Health (RO1AI064227)

Ellen A Robey

National Institutes of Health (T32AI100829)

Laura L McIntyre
Ashley R Hoover

Human Frontiers Fellowship

Silvia Ariotti

National Science Foundation (GRFP)

Zoë Steier

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were bred and maintained under pathogen-free conditions in an American Association of Laboratory Animal Care-approved facility at the University of California, Berkeley. The University of California, Berkeley Animal Use and Care Committee approved all procedures (Animal Care and Use Protocol #AUP-2016-07-9006).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.