The T cell receptor sequence influences the likelihood of T cell memory formation.

The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual's immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells. We find that hydrophobic complementarity-determining region (CDR)3 residues promote regulatory T cell fates in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features that promote the T cell transition from naive to memory. We quantify the extent of these features through our TCR scoring function "TCR-mem." Using TCR transduction experiments, we demonstrate that increased TCR-mem promotes T cell activation, even among T cells that recognize the same antigen. Our results reveal a common set of TCR sequence features that enable T cell activation and immunological memory.
Competing Interests: Declaration of interests M.E.B. is an equity holder in 3T Biosciences, Abata Therapeutics, and Kelonia Therapeutics, none of which directly affect this work. S.J.E. is a founder of ImmuneID, MAZE Therapeutics, Mirimus, and T-Scan Therapeutics and serves on the scientific advisory boards of Homology Medicines and MPM Capital, none of which directly affect this work. S.R. is a founder of Mestag, serves on the scientific advisory boards of Jannsen, Pfizer, and Sonoma, and consults for Abbvie, Nimbus, Biogen, Magnet, and Third Rock Ventures, none of which directly affect this work.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)