by Hebrew University of Jerusalem

Overview: Integration of multiple molecular mechanisms is needed to qualitatively explain nanoscale TCR activation patterns at early contacts. Credit: Frontiers in Immunology (2024). DOI: 10.3389/fimmu.2024.1412221

A research team behind a new study at the Hebrew University of Jerusalem has made an important breakthrough in understanding how immune cells known as T cells are activated.

By using an innovative approach called Bayesian metamodeling, the team combined data from advanced super-resolution microscopy techniques and stochastic computer simulations to reveal new, intricate patterns in early T-cell signaling.

The study is published in the journal Frontiers in Immunology.

T cells are key players in the immune system, responding specifically and efficiently to threats. Specifically, T cells act as sensitive agents that can identify the presence of infected or cancerous cells, and efficiently clear them. However, until now, existing microscopic models have only partially captured the molecular processes behind early T-cell activation, leaving gaps in our understanding.

The Hebrew University team’s metamodel brings these models together, drawing from data on how critical molecules—T-cell receptors (TCR), CD45, and Lck—interact and move at the initial points of contact between T cells and target cells.

A key discovery in a previous study from the Sherman lab, published in Cell Reports, is a nanoscale ring of activated TCR molecules, surprisingly appearing around the edge of initial T cell contacts and framed by a ring of CD45 molecules. This pattern could not be explained by current models of T cell activation. The researchers suggest that this pattern arises because Lck molecules, which help transmit signals between TCR and CD45, are restricted in their activity range. This limitation plays a crucial role in how TCRs get activated during the early immune response.

The team also analyzed how variations in Lck activity, specific antigen strengths, and forms of CD45 impact T-cell activation. These findings offer a more complete view of early T-cell signaling, with potential applications in understanding other complex cellular processes. Bayesian metamodeling, by integrating different models into a cohesive whole, offers a powerful tool for uncovering the hidden patterns that drive cellular behavior, with broad implications for immunology and medical research.

The team was led by Yair Neve-Oz from the Racah Institute of Physics and School of Computer Science and Engineering, Dr. Barak Raveh from the School of Computer Science and Engineering, and Eilon Sherman from the Racah Institute of Physics.

More information: Yair Neve-Oz et al, Bayesian metamodeling of early T-cell antigen receptor signaling accounts for its nanoscale activation patterns, Frontiers in Immunology (2024). DOI: 10.3389/fimmu.2024.1412221

Journal information:Frontiers in Immunology , Cell Reports

Provided by Hebrew University of Jerusalem

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