[HTML][HTML] Cross-reactive public TCR sequences undergo positive selection in the human thymic repertoire

M Khosravi-Maharlooei, A Obradovic… - The Journal of …, 2019 - Am Soc Clin Investig
The Journal of clinical investigation, 2019Am Soc Clin Investig
We studied human T cell repertoire formation using high-throughput T cell receptor β (TCRβ)
complementarity-determining region 3 (CDR3) sequencing in immunodeficient mice
receiving human hematopoietic stem cells (HSCs) and human thymus grafts. Replicate
humanized mice generated diverse and highly divergent repertoires. We observed
repertoire narrowing and increased CDR3β sharing during thymocyte selection. Whereas
hydrophobicity analysis implicated self-peptides in positive selection of the overall …
We studied human T cell repertoire formation using high-throughput T cell receptor β (TCRβ) complementarity-determining region 3 (CDR3) sequencing in immunodeficient mice receiving human hematopoietic stem cells (HSCs) and human thymus grafts. Replicate humanized mice generated diverse and highly divergent repertoires. We observed repertoire narrowing and increased CDR3β sharing during thymocyte selection. Whereas 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 CDR3βs, suggesting weaker interactions with self-peptides than were observed with 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–cross-reactive CDR3βs and for type 1 diabetes–associated autoreactive CDR3βs. Single-cell TCR sequencing showed increased sharing of CDR3αs compared with CDR3βs between mice. Our data collectively implicate preferential positive selection for shared human CDR3βs that are highly cross-reactive. Although previous studies suggested a role for recombination bias in producing “public” sequences in mice, our study is the first to our knowledge to demonstrate a role for thymic selection. Our results implicate positive selection for promiscuous TCRβ sequences that probably evade negative selection, given their low affinity for self-ligands, in the abundance of “public” human TCRβ sequences.
The Journal of Clinical Investigation