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Eric S. Huseby et al, Cell (2005); Nature Immunol. (2007),

Specificity. Eric S. Huseby et al, Cell (2005); Nature Immunol. (2007), compared the T cells of normal mice, with mice genetically engineered to present only one type of peptide in their thymus.

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Eric S. Huseby et al, Cell (2005); Nature Immunol. (2007),

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  1. Specificity Eric S. Huseby et al, Cell (2005); Nature Immunol. (2007), compared the T cells of normal mice, with mice genetically engineered to present only one type of peptide in their thymus. T cells selected in the thymus are challenged with an antigenic peptide, and reactive T cells identified. Does a reactive T cell remain reactive upon mutating the peptide’s amino acids? If mutations to an amino acid destroy reactivity with at least half the T cells, the amino-acid is labeled a “hot spot”. • Main results: • Single peptide selection: few hot spots – cross-reactive T cells • Many peptide selection: many hot spots – specific T cells

  2. Specificity to antigen peptide: • Single peptide: mutations don’t matter – cross-reactive T-cells • Many peptides: mutations destroy reactivity – specific T-cells

  3. Numerical results for hot-spots† mirror the experimental situation frequency †Hot-spots are defined as locations along the sequence, where mutations of a peptide amino acid destroy reactivity with more than half the reactive T cells

  4. Frustration during negative selection constrains TCR sequences One peptide Ep < E < EN selected

  5. Frustration during negative selection constrains TCR sequences One peptide selected

  6. Frustration during negative selection constrains TCR sequences One peptide selected Many peptides E > EN negatively selected Optimizing interactions with one peptide can lead to “bad” interactions with another – FRUSTRATION. Positive selection does not involve frustration.

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