Naive and memory T cells TCR-HLA-binding prediction

T cells recognize antigens through the interaction of their T cell receptor (TCR) with a peptide-major histocompatibility complex (pMHC) molecule. Following thymic-positive selection, TCRs in peripheral naive T cells are expected to bind MHC alleles of the host. Peripheral clonal selection is expected to further increase the frequency of antigen-specific TCRs that bind to the host MHC alleles. To check for a systematic preference for MHC-binding T cells in TCR repertoires, we developed Natural Language Processing-based methods to predict TCR-MHC binding independently of the peptide presented for Class I MHC alleles. We trained a classifier on published TCR-pMHC binding pairs and obtained a high area under curve (AUC) of over 0.90 on the test set. However, when applied to TCR repertoires, the accuracy of the classifier dropped. We thus developed a two-stage prediction model, based on large-scale naive and memory TCR repertoires, denoted TCR HLA-binding predictor (CLAIRE). Since each host carries multiple human leukocyte antigen (HLA) alleles, we first computed whether a TCR on a CD8 T cell binds an MHC from any of the host Class-I HLA alleles. We then performed an iteration, where we predict the binding with the most probable allele from the first round. We show that this classifier is more precise for memory than for naïve cells. Moreover, it can be transferred between datasets. Finally, we developed a CD4-CD8 T cell classifier to apply CLAIRE to unsorted bulk sequencing datasets and showed a high AUC of 0.96 and 0.90 on large datasets. CLAIRE is available through a GitHub at: https://github.com/louzounlab/CLAIRE, and as a server at: https://claire.math.biu.ac.il/Home.