TY - JOUR
T1 - Public T-Cell Receptors (TCRs) Revisited by Analysis of the Magnitude of Identical and Highly-Similar TCRs in Virus-Specific T-Cell Repertoires of Healthy Individuals
AU - Huisman, Wesley
AU - Hageman, Lois
AU - Leboux, Didier A. T.
AU - Khmelevskaya, Alexandra
AU - Efimov, Grigory A.
AU - Roex, Marthe C. J.
AU - Amsen, Derk
AU - Falkenburg, J. H. Frederik
AU - Jedema, Inge
N1 - Funding Information: This work was supported by Sanquin Research and Landsteiner Laboratory for Blood Cell research [PPO 15-37/Lnumber 2101]. This study was in part also supported by research funding from Stichting den Brinker (The Netherlands, Zeist) that made a donation to the Leukemia fund from the Bontius Foundation (Leiden University Medical Center). Publisher Copyright: Copyright © 2022 Huisman, Hageman, Leboux, Khmelevskaya, Efimov, Roex, Amsen, Falkenburg and Jedema.
PY - 2022/3/24
Y1 - 2022/3/24
N2 - Since multiple different T-cell receptor (TCR) sequences can bind to the same peptide-MHC combination and the number of TCR-sequences that can theoretically be generated even exceeds the number of T cells in a human body, the likelihood that many public identical (PUB-I) TCR-sequences frequently contribute to immune responses has been estimated to be low. Here, we quantitatively analyzed the TCR-repertoires of 190 purified virus-specific memory T-cell populations, directed against 21 epitopes of Cytomegalovirus, Epstein-Barr virus and Adenovirus isolated from 29 healthy individuals, and determined the magnitude, defined as prevalence within the population and frequencies within individuals, of PUB-I TCR and of TCR-sequences that are highly-similar (PUB-HS) to these PUB-I TCR-sequences. We found that almost one third of all TCR nucleotide-sequences represented PUB-I TCR amino-acid (AA) sequences and found an additional 12% of PUB-HS TCRs differing by maximally 3 AAs. We illustrate that these PUB-I and PUB-HS TCRs were structurally related and contained shared core-sequences in their TCR-sequences. We found a prevalence of PUB-I and PUB-HS TCRs of up to 50% among individuals and showed frequencies of virus-specific PUB-I and PUB-HS TCRs making up more than 10% of each virus-specific T-cell population. These findings were confirmed by using an independent TCR-database of virus-specific TCRs. We therefore conclude that the magnitude of the contribution of PUB-I and PUB-HS TCRs to these virus-specific T-cell responses is high. Because the T cells from these virus-specific memory TCR-repertoires were the result of successful control of the virus in these healthy individuals, these PUB-HS TCRs and PUB-I TCRs may be attractive candidates for immunotherapy in immunocompromised patients that lack virus-specific T cells to control viral reactivation.
AB - Since multiple different T-cell receptor (TCR) sequences can bind to the same peptide-MHC combination and the number of TCR-sequences that can theoretically be generated even exceeds the number of T cells in a human body, the likelihood that many public identical (PUB-I) TCR-sequences frequently contribute to immune responses has been estimated to be low. Here, we quantitatively analyzed the TCR-repertoires of 190 purified virus-specific memory T-cell populations, directed against 21 epitopes of Cytomegalovirus, Epstein-Barr virus and Adenovirus isolated from 29 healthy individuals, and determined the magnitude, defined as prevalence within the population and frequencies within individuals, of PUB-I TCR and of TCR-sequences that are highly-similar (PUB-HS) to these PUB-I TCR-sequences. We found that almost one third of all TCR nucleotide-sequences represented PUB-I TCR amino-acid (AA) sequences and found an additional 12% of PUB-HS TCRs differing by maximally 3 AAs. We illustrate that these PUB-I and PUB-HS TCRs were structurally related and contained shared core-sequences in their TCR-sequences. We found a prevalence of PUB-I and PUB-HS TCRs of up to 50% among individuals and showed frequencies of virus-specific PUB-I and PUB-HS TCRs making up more than 10% of each virus-specific T-cell population. These findings were confirmed by using an independent TCR-database of virus-specific TCRs. We therefore conclude that the magnitude of the contribution of PUB-I and PUB-HS TCRs to these virus-specific T-cell responses is high. Because the T cells from these virus-specific memory TCR-repertoires were the result of successful control of the virus in these healthy individuals, these PUB-HS TCRs and PUB-I TCRs may be attractive candidates for immunotherapy in immunocompromised patients that lack virus-specific T cells to control viral reactivation.
KW - CDR3 amino acid motifs
KW - TCR - T cell receptor
KW - TCR repertoire analysis
KW - V-D-J recombination
KW - computational analysis
KW - memory T cells (Tmem)
KW - public T cell receptors
KW - virus-specific T cell responses
UR - http://www.scopus.com/inward/record.url?scp=85127892551&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2022.851868
DO - https://doi.org/10.3389/fimmu.2022.851868
M3 - Article
C2 - 35401538
SN - 1664-3224
VL - 13
SP - 851868
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 851868
ER -