Crossreactive public TCR sequences undergo positive selection in the human thymic repertoire.

ABSTRACT: We investigated human T-cell repertoire formation using high throughput TCR? CDR3 sequencing in immunodeficient mice receiving human hematopoietic stem cells (HSCs) and human thymus grafts. Replicate humanized mice generated diverse and highly divergent repertoires. Repertoire narrowing and increased CDR3? sharing was observed during thymocyte selection. While hydrophobicity analysis implicated self-peptides in positive selection of the overall repertoire, positive selection favored shorter shared sequences that had reduced hydrophobicity at positions 6 and 7 of CDR3?s, suggesting weaker interactions with self-peptides than unshared sequences, possibly allowing escape from negative selection. Sharing was similar between autologous and allogeneic thymi and occurred between different cell subsets. Shared sequences were enriched for allo-crossreactive CDR3?s and for Type 1 diabetes-associated autoreactive CDR3?s. Single-cell TCR-sequencing showed increased sharing of CDR3?s compared to CDR3?s between mice. Our data collectively implicate preferential positive selection for shared human CDR3?s that are highly cross-reactive. While previous studies suggested a role for recombination bias in producing "public" sequences in mice, our study is the first to demonstrate a role for thymic selection. Our results implicate positive selection for promiscuous TCR? sequences that likely evade negative selection, due to their low affinity for self-ligands, in the abundance of "public" human TCR? sequences.

SUBMITTER: Khosravi-Maharlooei M 

PROVIDER: S-EPMC6546456 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature