Abstract
Adaptive immune recognition is mediated by the binding of peptide-human leukocyte antigen complexes by T cells. Positive selection of T cells in the thymus is a fundamental step in the generation of a responding T cell repertoire: only those T cells survive that recognize human peptides presented on the surface of cortical thymic epithelial cells. We propose that while this step is essential for optimal immune function, the process results in a defective T cell repertoire because it is mediated by self-peptides. To test our hypothesis, we focused on amino acid motifs of peptides in contact with T cell receptors. We found that motifs rarely or not found in the human proteome are unlikely to be recognized by the immune system just like the ones that are not expressed in cortical thymic epithelial cells or not presented on their surface. Peptides carrying such motifs were especially dissimilar to human proteins. Importantly, we present our main findings on two independent T cell activation datasets and directly demonstrate the absence of naïve T cells in the repertoire of healthy individuals. We also show that T cell cross-reactivity is unable to compensate for the absence of positively selected T cells. Additionally, we show that the proposed mechanism could influence the risk for different infectious diseases. In sum, our results suggest a side effect of T cell positive selection, which could explain the nonresponsiveness to many nonself peptides and could improve the understanding of adaptive immune recognition.
Highlights
The positive selection of T cells is an essential step in the formation of a responsive T cell repertoire
We propose a fundamental side effect of T cell positive selection on the recognition of nonself peptides: as positive selection is mediated by self-peptides, a large fraction of nonself peptides is not recognized by the immune system even if T cells are crossreactive
To test the predictions of our hypothesis, we focused on the immunogenicity of peptides that are presented by human leukocyte antigen (HLA)-I molecules, and the lack of T cell response cannot be explained by missing antigen presentation
Summary
The positive selection of T cells is an essential step in the formation of a responsive T cell repertoire. As T cell positive selection is mediated by TCEMs of self-peptides, we expected that it is less likely to find specific T cells in the repertoire for TCEMs that are 1) very rare or missing from human proteins, 2) not expressed in, or 3) not presented on the surface of cTECs. we expected that peptides carrying such motifs are less immunogenic. CTECs present a special set of peptides on the cell surface produced by the thymoproteasome and cathepsin L [6,7,8] Recognition of these cTEC-specific peptides by T cell precursors (called thymocytes) is essential for the formation of a functioning T cell repertoire. The immune system is still unable to recognize a large fraction of highly dissimilar peptides found in a wide variety of pathogens We propose that this phenomenon could be explained by the mechanism of T cell positive selection. As self-peptides mediate positive selection, the immune system is unable to recognize many nonself peptides, most of which are highly dissimilar to human peptides
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