RT Journal Article
SR Electronic
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
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.29.470325
DO 10.1101/2021.11.29.470325
A1 Wesley Huisman
A1 Lois Hageman
A1 Didier A.T. Leboux
A1 Alexandra Khmelevskaya
A1 Grigory A. Efimov
A1 Marthe C.J. Roex
A1 Derk Amsen
A1 J.H.F. Falkenburg
A1 Inge Jedema
YR 2021
UL http://biorxiv.org/content/early/2021/11/30/2021.11.29.470325.abstract
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 antigens 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.Significance statement Public T-cell responses, in which T cells expressing the same T-cell receptor (TCR) are found in different individuals, have been described. However, the magnitude of the contribution of these TCRs to immune responses, defined as prevalence within the population and frequencies within individuals, is not known. In this study we characterized and quantified public T-cell responses within virus-specific memory T cells of healthy individuals by determining identical and highly-similar TCRs recognizing the same antigen and sharing conserved CDR3 motifs. The magnitude of public T-cell responses was surprisingly high and we argue that these dominant TCRs with shared core-sequences could be utilized for diagnostic purposes and may provide attractive TCRs to be used for immunotherapy in immunocompromised patients.Competing Interest StatementThe authors have declared no competing interest.