Origin of the sharp boundary that discriminates positive and negative selection of thymocytes

Ashok Prasad, Julie Zikherman, Jayajit Das, Jeroen P. Roose, Arthur Weiss, Arup K. Chakraborty

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

T lymphocytes play a key role in adaptive immunity and are activated by interactions of their T cell receptors (TCR) with peptides (p) derived from antigenic proteins bound to MHC gene products. The repertoire of T lymphocytes available in peripheral organs is tuned in the thymus. Immature T lymphocytes (thymocytes) interact with diverse endogenous peptides bound to MHC in the thymus. TCR expressed on thymocytes must bind weakly to endogenous pMHC (positive selection) but must not bind too strongly to them (negative selection) to emerge from the thymus. Negatively selecting pMHC ligands bind TCR with a binding affinity that exceeds a sharply defined (digital) threshold. In contrast, there is no sharp threshold separating positively selecting ligands from those that bind too weakly to elicit a response. We describe results of computer simulations and experiments, which suggest that the contrast between the characters of the positive and negative selection thresholds originates in differences in the way in which Ras proteins are activated by ligands of varying potency. The molecular mechanism suggested by our studies generates hypotheses for how genetic aberrations may dampen the digital negative selection response, with concomitant escape of autoimmune T lymphocytes from the thymus.

Original languageEnglish
Pages (from-to)528-533
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number2
DOIs
StatePublished - 13 Jan 2009
Externally publishedYes

Keywords

  • Positive feedback
  • Ras activation
  • Signal transduction
  • T cell antigen receptor
  • Thymic development

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