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

Autor:	Khosravi-Maharlooei M; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA., Obradovic A; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA., Misra A; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA., Motwani K; Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA., Holzl M; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA., Seay HR; Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA., DeWolf S; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA., Nauman G; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA.; Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, New York, USA., Danzl N; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA., Li H; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA., Ho SH; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA., Winchester R; Division of Rheumatology, Department of Medicine., Shen Y; Center for Computational Biology and Bioinformatics, and., Brusko TM; Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA., Sykes M; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York, USA.; Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, New York, USA.; Department of Surgery, Columbia University Medical Center, Columbia University, New York, New York, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2019 Mar 28; Vol. 129 (6), pp. 2446-2462. Date of Electronic Publication: 2019 Mar 28.
DOI:	10.1172/JCI124358
Abstrakt:	We investigated human T-cell repertoire formation using high throughput TCRβ 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 CDR3β 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 CDR3βs, 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 CDR3βs and for Type 1 diabetes-associated autoreactive CDR3βs. Single-cell TCR-sequencing showed increased sharing of CDR3αs compared to CDR3βs between mice. Our data collectively implicate preferential positive selection for shared human CDR3βs 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 TCRβ sequences that likely evade negative selection, due to their low affinity for self-ligands, in the abundance of "public" human TCRβ sequences.
Databáze:	MEDLINE
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