Timing and duration of MHC I positive selection signals are adjusted in the thymus to prevent lineage errors

Nat Immunol. 2016 Dec;17(12):1415-1423. doi: 10.1038/ni.3560. Epub 2016 Sep 26.


Major histocompatibility complex class I (MHC I) positive selection of CD8+ T cells in the thymus requires that T cell antigen receptor (TCR) signaling end in time for cytokines to induce Runx3d, the CD8-lineage transcription factor. We examined the time required for these events and found that the overall duration of positive selection was similar for all CD8+ thymocytes in mice, despite markedly different TCR signaling times. Notably, prolonged TCR signaling times were counter-balanced by accelerated Runx3d induction by cytokines and accelerated differentiation into CD8+ T cells. Consequently, lineage errors did not occur except when MHC I-TCR signaling was so prolonged that the CD4-lineage-specifying transcription factor ThPOK was expressed, preventing Runx3d induction. Thus, our results identify a compensatory signaling mechanism that prevents lineage-fate errors by dynamically modulating Runx3d induction rates during MHC I positive selection.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / physiology*
  • Cell Differentiation
  • Cell Lineage
  • Cells, Cultured
  • Clonal Selection, Antigen-Mediated*
  • Core Binding Factor Alpha 3 Subunit / genetics
  • Core Binding Factor Alpha 3 Subunit / metabolism*
  • Cytokines / metabolism
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • Thymus Gland / immunology*
  • Transcription Factors


  • Core Binding Factor Alpha 3 Subunit
  • Cytokines
  • Histocompatibility Antigens Class I
  • Receptors, Antigen, T-Cell
  • Runx3 protein, mouse
  • Th-POK protein, mouse
  • Transcription Factors