How the thymus designs antigen-specific and self-tolerant T cell receptor sequences

Andrej Košmrlj, Abhishek K. Jha, Eric S. Huseby, Mehran Kardar, Arup K. Chakraborty

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

T lymphocytes (T cells) orchestrate adaptive immune responses that clear pathogens from infected hosts. T cells recognize short peptides (p) derived from antigenic proteins bound to protein products of the MHC genes. Recognition occurs when T cell receptor (TCR) proteins expressed on T cells bind sufficiently strongly to antigen-derived pMHC complexes on the surface of antigen-presenting cells. A diverse repertoire of self-pMHC-tolerant TCR sequences is shaped during development of T cells in the thymus by processes called positive and negative selection. Combining computational models and analysis of experimental data, we parsed the contributions of positive and negative selection to the design of TCR sequences that recognize antigenic peptides with specificity, yet also exhibit cross-reactivity. A dominant role for negative selection in mediating antigen specificity of mature T cells and a molecular mechanism for TCR recognition of antigen are described.

Original languageEnglish (US)
Pages (from-to)16671-16676
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number43
DOIs
StatePublished - Oct 28 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Statistical mechanics
  • T cell antigen specificity
  • Thymic selection

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