Spatial topology and competitive access differentially shape early T cell priming in the lymph node: an agent-based...

Area of Science:

• Immunology
• Computational Biology
• Systems Biology

Background:

• Adaptive immune activation requires naïve T cells to find antigen-presenting dendritic cells within lymph node microanatomy.
• Reduced T cell priming efficiency is often attributed to weak T cell receptor signaling.
• It remains unclear if priming failure stems from impaired signaling or limited access to dendritic cells.

Purpose of the Study:

• To investigate the role of lymph node architecture and cell trafficking in T cell priming.
• To determine whether limited access to antigen-bearing dendritic cells or signaling strength is the primary driver of priming failure.

Main Methods:

• Development of COORDINATE, a spatially explicit agent-based model of lymph node microanatomy.
• Integration of fibroblastic reticular cell topology, chemokine-guided migration, and competition for dendritic cell access into the model.

Main Results:

• Lymph node stromal architecture and cell migration patterns significantly influence T cell encounters with antigen.
• Competition for limited dendritic cell access can prevent a substantial fraction of T cells from forming productive contacts.
• Reduced T cell activation can result from failed clonal recruitment rather than diminished signaling upon contact.

Conclusions:

• Early T cell priming is an access-limited process influenced by spatial structure and cell competition.
• Endpoint measurements may conflate failure to access antigen with failure to activate.
• Enhancing early antigen access, not solely signaling strength, may be a strategy to improve adaptive immune responses.