Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 43, Pages 16671-16676Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0808081105
Keywords
statistical mechanics; T cell antigen specificity; thymic selection
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Funding
- National Institutes of Health (NIH) [1-PO1-AI071195-01]
- NIH Director's Pioneer award
- Beckman Young Investigator and Searle Scholar awards
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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 pMIHC 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.
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