Biology subjects

Akitsu, A.

Publications and source records attributed to Akitsu, A..

3 recordsLinked to original sources

bioRxiv2024

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Increasing evidence suggests that mechanical load on the {beta} T cell receptor (TCR) is crucial for recognizing the antigenic peptide-loaded major histocompatibility complex (pMHC) molecule. Our recent all-atom molecular dynamics (MD) simulations revealed that the inter-domain motion of the TCR is responsible for the load-induced catch bond behavior of the TCR-pMHC complex and peptide discrimination. To further examine the generality of the mechanism, we perform all-atom MD simulations of the B7 TCR under different conditions for comparison with our previous simulations of the A6 TCR. The two TCRs recognize the same pMHC and have similar interfaces with pMHC in crystal structures. We find that the B7 TCR-pMHC interface stabilizes under [~]15-pN load using a conserved dynamic allostery mechanism that involves the asymmetric motion of the TCR chassis. However, despite forming comparable contacts with pMHC as A6 in the crystal structure, B7 has fewer high-occupancy contacts with pMHC and exhibits higher mechanical compliance during the simulation. These results indicate that the dynamic allostery common to the TCR{beta} chassis can amplify slight differences in interfacial contacts into distinctive mechanical responses and nuanced biological outcomes.

biophysics↗

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↗

bioRxiv2022

Pre-T cell receptor Self-MHC Sampling Restricts Thymocyte Dedifferentiation

Summary paragraphProgramming T lymphocytes to distinguish self from non-self is a vital, multi-step process arising in the thymus1-4. Signalling through the pre-T cell receptor (preTCR), a CD3-associated heterodimer comprising an invariant pT chain and a clone-specific {beta} chain, constitutes a critical early checkpoint in thymocyte development within the {beta} T-cell lineage5, 6. Recent work demonstrates that preTCRs arrayed on double negative (DN) thymocytes, like {beta} TCRs appearing on double positive (DP) thymocytes, ligate peptides bound to MHC molecules (pMHC) on thymic stroma but via a different molecular docking strategy7-10. Here we show the consequences of those distinctive interactions for thymocyte progression, using synchronized fetal thymic progenitor cultures differing in the presence or absence of pMHC on support stroma, determining single cell transcriptomes at key thymocyte developmental transitions. Although MHC negative stroma fosters {beta} T lymphocyte differentiation, the absence of pMHC-preTCR interplay leads to deviant thymocyte transcriptional programming associated with de-differentiation. Highly proliferative DN and DP subsets with antecedent characteristics of T cell lymphoblastic and myeloid malignancies emerge. Thus, at least in vitro, beyond fostering {beta} chain repertoire broadening for subsequent {beta} TCR utilization, preTCR-pMHC interaction limits cellular plasticity to facilitate normal thymocyte differentiation and proliferation that, if absent, introduces significant developmental vulnerabilities.

immunology↗