Fig. 9

Proposed model of TCRB rearrangement and selection. a In healthy donors (HD) a random combination of VDJ genes undergoes rearrangement (see Supplementary Fig. 12 for a more detailed explanation of the rearrangement process), yielding a pre-selection repertoire of short and long TCRB CDR3s. Positive selection enriches for short TCRB CDR3s, and negative selection deletes most of the autoreactive clonotypes (orange), generating a polyreactive post-selection repertoire (true naive cells). b In type 1 diabetes (T1D) patients, alterations in TCRB rearrangement cause the generation of higher frequencies of shorter TCRB CDR3s, bearing long deletions and short insertions. Positive selection enriches for shorter TCRs, and therefore the input of TCRB chains into negative selection is higher than in healthy donors. Published alterations in negative selection suggest that in T1D a notable proportion of autoreactive clonotypes do not get deleted. The final outcome is a more diverse post-selection repertoire, enriched in shorter clonotypes, highly shared and containing autoreactive clonotypes. Black dots in clonotypes represent the conserved C and F amino acids in the 5′ and 3′ ends of the TCRB CDR3, respectively. White dots represent amino acids other than the conserved C and F. To ease the interpretation of the model only the CDR3B loop of the TCRB chain is shown, and the rearrangement of the TCRA chain has been omitted