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Fig. 4 | Genome Medicine

Fig. 4

From: Exploring the pre-immune landscape of antigen-specific T cells

Fig. 4

HLA-mediated selection of TCRs and epitope-specific clonal expansions. a Box and swarm plots show the distributions of ratios of the observed and expected numbers of rearrangements for different combinations of donor HLAs (according to genotypes from Emerson et al.) and HLAs associated with specific TCRs (according to epitope restrictions from VDJdb). Each dot represents the ratio of the total number of TCR rearrangements specific for epitopes restricted by a given HLA and the expected number of TCR rearrangements, computed with the assumption of independence between TCR restriction and donor HLA (see insert with formula). Red dots indicate matches between donor HLAs and rearranged TCRs. The inset box plot shows observed to expected ratios for matched and mismatched HLAs (**, P = 0.004, Mann–Whitney U test). Only HLA alleles present in at least 30 immune repertoire samples with at least 100 associated TCR sequences in VDJdb were selected. b Log10-transformed P values for VDJdb TCR enrichments in groups of samples with different HLAs (computed using a hypergeometric test comparing the number of times a given TCR was found in samples with and without a certain HLA). Left panel: enrichment P values plotted against rearrangement probabilities for sample groups that either do (red dots) or do not (black dots) have an HLA matching a given TCR (P > 10−4 shown with density plot). Right panel: the same data with epitopes grouped by source. P values were adjusted for multiple testing using the Benjamini–Hochberg method (TCRs with Padjusted > 0.05 were filtered out). c Distribution of the log2 read frequency ratios of CMV-specific clonotypes in HLA-matched and HLA-mismatched samples from CMV-seronegative (CMV, red), CMV-seropositive (CMV+, blue), and CMV-indeterminate donors (Unknown, green). As in previous panels, HLA matching indicates the presence of at least one HLA corresponding to the restriction element for a given TCR. All three distributions are significantly different: P = 6 × 10−11 for CMV-seropositive versus CMV-seronegative donors; P = 4 × 10−4 for CMV-seropositive versus CMV-indeterminate donors; P = 8 × 10−13 for CMV-seronegative versus CMV-indeterminate donors; Kolmogorov–Smirnov test. d Numbers of EBV-specific clonotypes constituting higher or lower fractions of reads in HLA-matched versus HLA-mismatched samples. Only HLA alleles associated with EBV-specific clonotypes according to VDJdb are shown (HLA-B*44 was discarded, as it was represented by just three sequences). Error bars show 95% confidence intervals (binomial distribution)

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