A timeline demarcating two waves of clonal deletion and Foxp3 upregulation during thymocyte development

Immunol Cell Biol. 2016 Apr;94(4):357-66. doi: 10.1038/icb.2015.95. Epub 2015 Oct 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / immunology
  • Cell Differentiation*
  • Cell Proliferation
  • Cells, Cultured
  • Clonal Selection, Antigen-Mediated*
  • DNA-Binding Proteins / metabolism
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, CCR7 / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Thymocytes / immunology*
  • Thymus Gland / anatomy & histology
  • Thymus Gland / immunology*
  • Transcription Factors / metabolism
  • Up-Regulation

Substances

  • Autoantigens
  • CCR7 protein, human
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, CCR7
  • Transcription Factors
  • Zfpn1a2 protein, mouse