Download One peptide selected Frustration during negative selection

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
• Specificity to antigen peptide:
– Single peptide: mutations don’t matter – cross-reactive T-cells
– Many peptides: mutations destroy reactivity – specific T-cells
frequency
Numerical results for hot-spots† mirror the experimental situation
†
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
Frustration during negative selection constrains TCR sequences
One peptide
T C R
Ep < E < EN
selected
Frustration during negative selection constrains TCR sequences
One peptide
T C R
EN  i U (li , ji )  E p
selected
Frustration during negative selection constrains TCR sequences
One peptide
T C R
EN  i U (li , ji )  E p
selected
Many peptides
T C R
E > EN
negatively selected
Optimizing interactions with one peptide can lead to “bad” interactions with another –
FRUSTRATION.
Positive selection does not involve frustration.