Authors
Akitsu, A., Tan, K., Mallis, R. J., Booker, M. A., Duke-Cohan, J. S., Brazin, K. N., Kirkpatrick, E. H., Parkins, A. N., Aryal, S., Cinella, V., Lee, J. J., Uberoy, K. I., Koenig, J. K., Biddle, M., Messier, C. M., Lizotte, P. H., Tolstorukov, M. Y., Hwang, W., Lang, M. J., Reinherz, E. L.
Abstract
Memory T cells endow the mammalian host with an essential form of adaptive immunity that generates durable and rapid protection following re-exposure to an infectious pathogen or a cancerous transformation. How naive CD8+ T cells develop into memory T cells that bifurcate into long-lived central (TCM) versus effector (TEM) subsets after such an antigen encounter remains ill-defined at the molecular level. To address this gap, here we dissect the functional T-cell receptor (TCR) repertoire of 242 murine CD8+ TCR{beta} clonotypes specific for the peptide-major histocompatibility complex molecule (pMHC) comprising an immunodominant influenza A virus (IAV) oligopeptide epitope NP366-374 presented by H-2Db. Using single-cell transcriptomics with TCR sequencing, biophysical measurements of force-dependent TCR-pMHC interactions, in vivo memory development, and structural analyses, we integrate these data to define relationships between signaling polarity and memory fate. We find that TCM and TEM polarities are reflected in distinct subunit-related mechanotransduction biases: TCM-associated TCRs favor TCR{beta}-driven pMHC engagement, whereas TEM-associated TCRs preferentially favor TCR-driven pMHC engagement. Moreover, "bipolar" clonotypes (TBP) capable of generating both memory subsets exhibit more balanced signaling, the largest average clonal expansions, and broadest heterosubtypic crossreactivities. By contrast, variegated TCM TCR sequences foster mostly clonal singlets with the greatest IAV mutant recognition potential within the overall memory repertoire, thus revealing two complementary memory niche crossreactivity strategies. Weak, force-sensitive TCR bonds are pervasive for this entire repertoire, being most conspicuous amongst TCM clonotypes. At the atomic level, highly nuanced variation in TCR{beta} bonding to either peptide and/or MHC modulates mechanical load transmission across the holoreceptor's ectodomains, transmembrane segments, and CD3 cytoplasmic tails to differentially influence downstream tyrosine phosphorylation and memory development. Collectively, TCR diversity anticipates epitope-specific pathogen evolution, whereas divergent TCR signaling regulates memory fate with implications for adoptive T-cell immunotherapies seeking to maximize persistence and minimize functional exhaustion.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Nov 2025.
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