Biology subjects

Booker, M. A.

Publications and source records attributed to Booker, M. A..

3 recordsLinked to original sources

bioRxiv2025

Atomistic TCR-ligand interactions instruct memory T-cell differentiation

Memory CD8 T cells provide durable protection against recurrent infection and cancer, but how distinct memory fates are specified remains unclear. Here, we define the functional landscape of 242 murine CD8 TCR{beta} clonotypes specific for influenza NP366-374/H-2D ligand (pMHC) by integrating single-cell transcriptomics and TCR sequencing with force-dependent biophysics, structural analysis, and in vivo investigation of memory development. Fate essentially tracks with TCR mechanotransduction: TCM-associated clonotypes preferentially engage pMHC through TCR{beta}, whereas TEM-associated clonotypes preferentially engage through TCR. Clonotypes with balanced, bipolar signaling generate both memory subsets, optimize expansion, and display broad heterosubtypic crossreactivity but with exhaustion susceptibility. In contrast, diverse TCM clonotypes are largely clonal singlets with considerable mutant-epitope recognition in aggregate and stemness preservation, revealing complementary strategies for immunodefense coverage. Atomistically, subtle pMHC contact differences and load transmission through the TCR holoreceptor appear to tune phosphorylation, memory differentiation, and functional durability, features applicable to adoptive T-cell immunotherapies.

immunology↗

bioRxiv2023

Parsing digital or analogue TCR performance through piconewton forces

{beta} T-cell receptors (TCRs) recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP366-374 /Db and PA224-233/Db, respectively) following in vivo influenza A virus infection were studied with optical tweezers. While certain NP repertoire CD8 T lymphocytes require many ligands for activation, others are digital, needing just few. Conversely, all PA TCRs perform digitally, exhibiting pronounced bond lifetime increases through sustained, energizing volleys of structural transitioning. Optimal digital performance is superior in vivo, correlating with ERK phosphorylation, CD3 loss, and activation marker upregulation in vitro. Given neoantigen array paucity, digital TCRs are likely critical for immunotherapies. One Sentence SummaryQuality of ligand recognition in a T-cell repertoire is revealed through application of physical load on clonal T-cell receptor (TCR)-pMHC bonds

immunology↗

bioRxiv2018

Non-neutral evolution of H3.3-encoding genes occurs without alterations in protein sequence

Histone H3.3 is a developmentally essential variant encoded by two independent genes in human (H3F3A and H3F3B). While this two-gene arrangement is evolutionarily conserved, its origins and function remain unknown. Phylogenetics, synteny and gene structure analyses of the H3.3 genes from 32 metazoan genomes indicate independent evolutionary paths for H3F3A and H3F3B. While H3F3B bears similarities with H3.3 genes in distant organisms and with canonical H3 genes, H3F3A is sarcopterygian-specific and evolves under strong purifying selection. Additionally, H3F3B codon-usage preferences resemble those of broadly expressed genes and cell differentiation-induced genes, while codon-usage of H3F3A resembles that of cell proliferation-induced genes. We infer that H3F3B is more similar to the ancestral H3.3 gene and likely evolutionarily adapted for broad expression pattern in diverse cellular programs, while H3F3A adapted for a subset of gene expression programs. Thus, the arrangement of two independent H3.3 genes facilitates fine-tuning of H3.3 expression across cellular programs.

evolutionary biology↗