T cells are defined by a heterodimeric surface receptor, the T cell receptor (TCR), that mediates recognition of pathogen-associated epitopes through interactions with peptide and major histocompatibility complexes (pMHCs). TCRs are generated by genomic rearrangement of the germline TCR locus, a process termed V(D)J recombination, that has the potential to generate marked diversity of TCRs (estimated to range from 1015 (ref. 1) to as high as 1061 (ref. 2) possible receptors). Despite this potential diversity, TCRs from T cells that recognize the same pMHC epitope often share conserved sequence features, suggesting that it may be possible to predictively model epitope specificity. Here we report the in-depth characterization of ten epitope-specific TCR repertoires of CD8+ T cells from mice and humans, representing over 4,600 in-frame single-cell-derived TCRαβ sequence pairs from 110 subjects. We developed analytical tools to characterize these epitope-specific repertoires: a distance measure on the space of TCRs that permits clustering and visualization, a robust repertoire diversity metric that accommodates the low number of paired public receptors observed when compared to single-chain analyses, and a distance-based classifier that can assign previously unobserved TCRs to characterized repertoires with robust sensitivity and specificity. Our analyses demonstrate that each epitope-specific repertoire contains a clustered group of receptors that share core sequence similarities, together with a dispersed set of diverse ‘outlier’ sequences. By identifying shared motifs in core sequences, we were able to highlight key conserved residues driving essential elements of TCR recognition. These analyses provide insights into the generalizable, underlying features of epitope-specific repertoires and adaptive immune recognition.
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We would like to thank the St Jude Children’s Research Hospital Animal Resource Center’s staff for their support and excellent animal care. We thank G. Lennon for the help with single-cell sorting. We thank the Hartwell Center at St Jude for sequencing support. We also thank M. Morris, L. McLaren, T. H. Oguin III, W. Awad, A. Zamora, D. Boyd, X. Guo, S. Valkenburg, E. Grant, N. Bird and N. Mifsud for their help in conducting experiments and preparation of the manuscript. The work was supported by NIH grant AI107625 and ALSAC (to P.G.T.), FHCRC internal development funding to P.B., and an NHMRC Program Grant (1071916) to K.K. and N.L.L. N.L.L. is the recipient of a Sylvia and Charles Viertel Senior Medical Research Fellowship. E.B.C. is an NHMRC Peter Doherty Fellow and K.K. is an NHMRC SRF Level B Fellow. G.C.W. was the recipient of National Institute on Aging (NIA) K23 AG033113, NIA P30 AG021334, John A. Hartford Foundation’s Center of Excellence in Geriatric Medicine Scholars Award, and Johns Hopkins Biology of Healthy Aging Program.
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