Bayesian metamodeling of early T-cell antigen receptor signaling accounts for its nanoscale activation patterns.

Autor:	Neve-Oz Y; Racah Institute of Physics, The Hebrew University, Jerusalem, Israel.; School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel., Sherman E; Racah Institute of Physics, The Hebrew University, Jerusalem, Israel., Raveh B; School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Oct 25; Vol. 15, pp. 1412221. Date of Electronic Publication: 2024 Oct 25 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1412221
Abstrakt:	T cells respond swiftly, specifically, sensitively, and robustly to cognate antigens presented on the surface of antigen presenting cells. Existing microscopic models capture various aspects of early T-cell antigen receptor (TCR) signaling at the molecular level. However, none of these models account for the totality of the data, impeding our understanding of early T-cell activation. Here, we study early TCR signaling using Bayesian metamodeling, an approach for systematically integrating multiple partial models into a metamodel of a complex system. We inform the partial models using multiple published super-resolution microscopy datasets. Collectively, these datasets describe the spatiotemporal organization, activity, interactions, and dynamics of TCR, CD45 and Lck signaling molecules in the early-forming immune synapse, and the concurrent membrane alterations. The resulting metamodel accounts for a distinct nanoscale dynamic pattern that could not be accounted for by any of the partial models on their own: a ring of phosphorylated TCR molecules, enriched at the periphery of early T cell contacts and confined by a proximal ring of CD45 molecules. The metamodel suggests this pattern results from limited activity range for the Lck molecules, acting as signaling messengers between kinetically-segregated TCR and CD45 molecules. We assessed the potential effect of Lck activity range on TCR phosphorylation and robust T cell activation for various pMHC:TCR association strengths, in the specific setting of an initial contact. We also inspected the impact of localized Lck inhibition via Csk recruitment to pTCRs, and that of splicing isoforms of CD45 on kinetic segregation. Due to the inherent scalability and adaptability of integrating independent partial models via Bayesian metamodeling, this approach can elucidate additional aspects of cell signaling and decision making. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Neve-Oz, Sherman and Raveh.)
Databáze:	MEDLINE
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