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

Abstract

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.

Counting is Almost All You Need

“…Some TCRs are highly abundant in different individuals (25), and have initial production probability (14; 3). Therefore, positively selected TCRs exist in various frequencies in positive immune repertoires, some especially common ones might appear randomly in negative instances as well.…”

“…Real TCRs have a scale free distribution. Some TCRs are public TCRs and are very common (25), and others are very rare. The pool size of positive and negative TCRs to draw from is also vastly different in size.…”

Amino acids at position 5 in the peptide/MHC binding region of a public virus‐specific TCR are completely inter‐changeable without loss of function

“…charge, hydrophobicity, and size). Position 5 of this CDR3β sequence [CASSxQGGNYGYTF], was recently identified as highly variable since 11 different, but highly‐similar TCRs, were found ex vivo in EBV‐LMP2 FLY ‐specific T‐cell populations from healthy individuals [16]. It was reported before that TCRs with a cysteine [C] in the CDR3β sequence would be dysfunctional and CDR3β sequences with positively charged and hydrophobic amino acids are disfavored [11].…”

“…The TCRαchains are generated similarly, with the exception of a D gene, resulting in V-J reading frames [2]. Gene segment rearrangements could potentially generate a repertoire of 10 15 -10 20 unique TCRs (3). The Complementary Determining Regions (CDRs) are the sequences in the TCR that form loops and are responsible for the interaction with the peptide and HLA molecule.…”

T cell receptor convergence is an indicator of antigen-specific T cell response in cancer immunotherapies

“…While little is known about the functional impact of TCR convergence, codon degeneracy has been widely studied( 6, 7 ). The fact that the number of three-nucleotides codons (64) exceeds the number of encoding amino acids (20) provides the basis of codon degeneracy. The distribution of degeneracy among the 20 encoding amino acids is uneven.…”