1. A timeline demarcating two waves of clonal deletion and Foxp3 upregulation during thymocyte development.
- Author
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Hu DY, Yap JY, Wirasinha RC, Howard DR, Goodnow CC, and Daley SR
- Subjects
- Animals, Autoantigens immunology, Cell Proliferation, Cells, Cultured, DNA-Binding Proteins metabolism, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, CCR7 metabolism, Thymus Gland anatomy & histology, Transcription Factors metabolism, Up-Regulation, Cell Differentiation, Clonal Selection, Antigen-Mediated, T-Lymphocytes, Regulatory immunology, Thymocytes immunology, Thymus Gland immunology
- Abstract
Thymocytes that bind strongly to self-antigens are prevented from becoming naive T cells by several mechanisms. They undergo clonal deletion at two stages of development; wave 1 in immature thymocytes lacking the medulla-homing chemokine receptor, CCR7, or wave 2 in more mature CCR7(+) thymocytes. Alternatively, self-reactive thymocytes upregulate Foxp3 to become T-regulatory cells. Here, we describe the differential timing of the two waves of deletion and Foxp3 upregulation relative to the immature proliferating stage. Proliferating thymocytes were pulse-labeled in normal C57BL/6 mice with 5-ethynyl-2'-deoxyuridine (EdU). Thymocytes progressed into wave 1 (CCR7(-)) and wave 2 (CCR7(+)) of clonal deletion ~2 and 5 days after proliferation, respectively. Foxp3 upregulation occurred between 4 and 8 days after proliferation, predominantly in thymocytes with a Helios(+) CCR7(+) phenotype. These findings establish a timeline that suggests that wave 1 of clonal deletion occurs in the thymic cortex, whereas wave 2 and Foxp3 upregulation both occur in the thymic medulla.
- Published
- 2016
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