Quantifying how TCR sequence variation affects T cell fate at single-cell resolution

Abstract Mucosal-Associated Invariant T (MAIT) and Natural Killer (NKT) cells demonstrate that some cell transcriptional fates are driven by the antigen receptor (TCR). Though activation through TCR is integral to differentiation, contribution of sequence features other remains yet be defined. In this study, we identify how αβ V(D)J recombination affects differentiation at single-cell resolution. By applying Canonical Correlation Analysis (CCA) 340,557 clones collected from 256 individuals, define a set scoring functions quantify fate predispositions conferred TCR. Unsurprisingly, strongest correspond cognate peptide presentation molecules: MR1- or CD1d-restricted PLZFhigh innate-like (MAIT/NKT) (72.6-fold increase in likelihood for top percentile compared bottom TCRs, AUC = 0.85) MHC class I-restricted CD8 versus II-restricted CD4 (18.7-fold increase, 0.75). However, our results also uncover hydrophobic CDR3 residues promote regulatory states both lineages, preferred thymic positive selection continue memory formation periphery. Applying 10× dextramer-labeled reveals not all antigen-specific TCRs equally capable mounting an effector response. Even among recognize same antigen, biophysical variation directs which undergo reprogramming form immunological memory. Supported grant NIH (T32GM007753)