TY - JOUR
T1 - Determinants governing T cell receptor α/β-chain pairing in repertoire formation of identical twins
AU - Tanno, Hidetaka
AU - Gould, Timothy M.
AU - McDaniel, Jonathan R.
AU - Cao, Wenqiang
AU - Tanno, Yuri
AU - Durrett, Russell E.
AU - Park, Daechan
AU - Cate, Steven J.
AU - Hildebrand, William H.
AU - Dekker, Cornelia L.
AU - Tian, Lu
AU - Weyand, Cornelia M.
AU - Georgiou, George
AU - Goronzy, Jörg J.
N1 - Funding Information:
Grant RP160015), Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad, and Uehara Memorial Foundation Research Fellowship. We thank the study participants and the staff of the Stanford–Lucile Packard Vaccine Program for conducting the twin study; the Stanford Clinical and Translational Research Unit provided resources through NIH–National Center for Advancing Translational Sciences–Clinical and Translational Science Award Grant UL1 TR001085. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Cancer Prevention and Research Institute of Texas.
Funding Information:
We thank the Genome Sequencing and Analysis Facility at the University of Texas at Austin for performing Illumina sequencing. This work was supported by NIH Grants U19 AI057266 (to G.G. and J.J.G.) and R01 AI129191 (to J.J.G.) and US Defense Threat Reduction Agency Grant HDTRA1-12-C-0105 (to G.G.). H.T. was supported by University of Texas Health Innovation for Cancer Prevention Research Training Program Postdoctoral Fellowship (Cancer Prevention and Research Institute of Texas Grant RP160015), Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad, and Uehara Memorial Foundation Research Fellowship. We thank the study participants and the staff of the Stanford?Lucile Packard Vaccine Program for conducting the twin study; the Stanford Clinical and Translational Research Unit provided resources through NIH?National Center for Advancing Translational Sciences?Clinical and Translational Science Award Grant UL1 TR001085. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Cancer Prevention and Research Institute of Texas.
Funding Information:
ACKNOWLEDGMENTS. We thank the Genome Sequencing and Analysis Facility at the University of Texas at Austin for performing Illumina sequencing. This work was supported by NIH Grants U19 AI057266 (to G.G. and J.J.G.) and R01 AI129191 (to J.J.G.) and US Defense Threat Reduction Agency Grant HDTRA1-12-C-0105 (to G.G.). H.T. was supported by University of Texas Health Innovation for Cancer Prevention Research Training Program Postdoctoral Fellowship (Cancer Prevention and Research Institute of Texas
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/1/7
Y1 - 2020/1/7
N2 - The T cell repertoire in each individual includes T cell receptors (TCRs) of enormous sequence diversity through the pairing of diverse TCR α- and β-chains, each generated by somatic recombination of paralogous gene segments. Whether the TCR repertoire contributes to susceptibility to infectious or autoimmune diseases in concert with disease-associated major histocompatibility complex (MHC) polymorphisms is unknown. Due to a lack in high-throughput technologies to sequence TCR α–β pairs, current studies on whether the TCR repertoire is shaped by host genetics have so far relied only on single-chain analysis. Using a high-throughput single T cell sequencing technology, we obtained the largest paired TCRαβ dataset so far, comprising 965,523 clonotypes from 15 healthy individuals including 6 monozygotic twin pairs. Public TCR α- and, to a lesser extent, TCR β-chain sequences were common in all individuals. In contrast, sharing of entirely identical TCRαβ amino acid sequences was very infrequent in unrelated individuals, but highly increased in twins, in particular in CD4 memory T cells. Based on nucleotide sequence identity, a subset of these shared clonotypes appeared to be the progeny of T cells that had been generated during fetal development and had persisted for more than 50 y. Additional shared TCRαβ in twins were encoded by different nucleotide sequences, implying that genetic determinants impose structural constraints on thymic selection that favor the selection of TCR α–β pairs with entire sequence identities.
AB - The T cell repertoire in each individual includes T cell receptors (TCRs) of enormous sequence diversity through the pairing of diverse TCR α- and β-chains, each generated by somatic recombination of paralogous gene segments. Whether the TCR repertoire contributes to susceptibility to infectious or autoimmune diseases in concert with disease-associated major histocompatibility complex (MHC) polymorphisms is unknown. Due to a lack in high-throughput technologies to sequence TCR α–β pairs, current studies on whether the TCR repertoire is shaped by host genetics have so far relied only on single-chain analysis. Using a high-throughput single T cell sequencing technology, we obtained the largest paired TCRαβ dataset so far, comprising 965,523 clonotypes from 15 healthy individuals including 6 monozygotic twin pairs. Public TCR α- and, to a lesser extent, TCR β-chain sequences were common in all individuals. In contrast, sharing of entirely identical TCRαβ amino acid sequences was very infrequent in unrelated individuals, but highly increased in twins, in particular in CD4 memory T cells. Based on nucleotide sequence identity, a subset of these shared clonotypes appeared to be the progeny of T cells that had been generated during fetal development and had persisted for more than 50 y. Additional shared TCRαβ in twins were encoded by different nucleotide sequences, implying that genetic determinants impose structural constraints on thymic selection that favor the selection of TCR α–β pairs with entire sequence identities.
KW - Major histocompatibility complex
KW - Monozygotic twins
KW - Single-cell sequencing
KW - T cell repertoire
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U2 - 10.1073/pnas.1915008117
DO - 10.1073/pnas.1915008117
M3 - Article
C2 - 31879353
AN - SCOPUS:85077659516
SN - 0027-8424
VL - 117
SP - 532
EP - 540
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
ER -