Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Zoë Steier
Department of Bioengineering, University of California, Berkeley, Berkeley, United States
Laura L McIntyre
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Shraddha Pandey
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
James Kaminski
Center for Computational Biology, University of California, Berkeley, Berkeley, United States
Ashley R Hoover
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Silvia Ariotti
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Aaron Streets
Department of Bioengineering, University of California, Berkeley, Berkeley, United States; Center for Computational Biology, University of California, Berkeley, Berkeley, United States; Chan Zuckerberg Biohub, San Francisco, United States
Department of Bioengineering, University of California, Berkeley, Berkeley, United States; Center for Computational Biology, University of California, Berkeley, Berkeley, United States; Chan Zuckerberg Biohub, San Francisco, United States; Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, United States; Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
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 T cell receptor (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 downregulate TCR sensitivity more slowly during positive selection, and associate membrane ion channel expression with thymocyte self-reactivity and progress through positive selection.
