Abstract
The T-cell receptor (TCR) repertoire is generated in a semistochastic process of gene recombination and pairing of TCRα to TCRβ chains with the estimated total TCR diversity of >108. Despite this high diversity, similar or identical TCR chains are found to recur in immune responses. Here, we analyzed the thymic generation of TCR sequences previously associated with recognition of self- and nonself-antigens, represented by sequences associated with autoimmune diabetes and HIV, respectively. Unexpectedly, in the CD4+ compartment TCRα chains associated with the recognition of self-antigens were generated in significantly higher numbers than TCRα chains associated with the recognition of nonself-antigens. The analysis of the circulating repertoire further showed that these chains are not lost in negative selection nor predominantly converted to the regulatory T-cell lineage. The high abundance of self-reactive TCRα chains in multiple individuals suggests that the human thymus has a predilection to generate self-reactive TCRα chains independently of the HLA-type and that the individual risk of autoimmunity may be modulated by the TCRβ repertoire associated with these chains.
Highlights
T-cell functionality is dependent on antigen recognition by a specific T-cell receptor (TCR), a heterodimeric cell surface receptor that binds to a complex formed by a peptide antigen in the groove of an HLAmolecule
Two of the donors (A and B) were mono zygotic twins. Their TCR repertoires showed a genetic impact in the V and J gene usage and in the generation of junctional sequences, but not in thymic selection [15]
Human immunodeficiency virus increases the risk of systemic autoimmunity even when viral replication is suppressed [35,36], while the current outbreak of COVID-19 is associated with autoimmune manifesta tions [37,38]
Summary
T-cell functionality is dependent on antigen recognition by a specific T-cell receptor (TCR), a heterodimeric cell surface receptor that binds to a complex formed by a peptide antigen in the groove of an HLAmolecule. Structurally the hy pervariable loops encoded by the CDR3 sequences are mainly respon sible for binding to the antigenic peptide, and likely to be the most important determinants of specificity [6] Given this high diversity, the default expectation has been that the TCR repertoire in each individual would be largely unique, or private. A large and growing body of research has shown that different individuals often use similar or same TCRs in antigen recognition at least for one chain of the heterodimer, whether the specificity be against viral, self- or tumor proteins [7,8] This phenomenon of shared, or public clones has been especially prominent in chronic or latent viral in fections, such as cytomegalovirus or herpes simplex virus [9].
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