Extended Data Fig. 7. Cross-reactivity distance C model.

Amino acid position dependent factor (a) and substitution matrix (b) of cross-reactivity model based on T cell receptor (TCR) cross-reactivity to strong (CMV) and weak (gp100) ${\mathbf{p}}^{\text{WT}}$s and single amino acid substituted ${\mathbf{p}}^{\text{MT}}$s (Fig. 3d, e). (c) Correlation of substitution-induced differential MHC-I binding ($\log \left(A\right)$ = $K_{\mathrm{d}}^{\mathrm{WT}}/K_{\mathrm{d}}^{\mathrm{MT}}$) and substitution induced differential TCR activation ($\log \left(C\right)$ = $\mathrm{E}{\mathrm{C}}_{50}^{\mathrm{MT}}/\mathrm{E}{\mathrm{C}}_{50}^{\mathrm{WT}}$) for all model ${\mathbf{p}}^{\text{WT}}$-TCR pairs and single amino acid substituted ${\mathbf{p}}^{\text{MT}}$s. $K_{\mathrm{d}}^{\mathrm{WT}}$ and $K_{\mathrm{d}}^{\mathrm{WT}}$ determined through computational predictions of ${\mathbf{p}}^{\text{WT}}$ and ${\mathbf{p}}^{\text{MT}}$ binding to HLA-A*02:01 (CMV, gp100 peptides) and HLA-B*27:05 (tumour neopeptide) with Net MHC 3.4. ${\mathrm{EC}}_{50}^{\text{MT}}$ and ${\mathrm{EC}}_{50}^{\mathrm{WT}}$ measured experimentally through ${\mathbf{p}}^{\text{WT}}$ and ${\mathbf{p}}^{\text{MT}}$ reactivity to TCRs. n = individual peptide-TCR measurements. P values by two-tailed Pearson correlation (c).

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