T-cell microvilli simulations show operation near packing limit and impact on antigen recognition

Abstract

T-cells are immune cells that continuously scan for foreign-derived antigens on the surfaces of nearly all cells, termed antigen presenting cells (APCs). They do this by dynamically extending numerous protrusions called microvilli (MV) that contain T-cell receptors (TCRs) towards the APC surface in order to scan for antigens. The number, size, and dynamics of these MV, and the complex multi-scale topography that results, play a yet unknown role in antigen recognition. We develop an anatomically informed model of the T-cell/APC interface to elucidate the role of MV dynamics in antigen sensitivity and discrimination. We find that MV surveillance reduces antigen sensitivity compared to a completely flat interface unless MV are stabilized in an antigen-dependent manner and find that MV have only a modest impact on antigen discrimination. The model highlights that MV contacts optimise the competing demands of fast scanning speeds of the APC surface with antigen sensitivity and that T-cells operate their MV near the interface packing limit. Finally, we find that observed MV contact lifetimes can be largely influenced by conditions in the T-cell/APC interface with these lifetimes often being longer than the simulation or experimental observation period. The work highlights the role of MV in antigen recognition.Significance StatementT-cells search for foreign-derived antigens on the surface of antigen presenting cells (APC) by dynamically extending tubular protrusions called microvilli (MV) which form membrane close-contacts. Although known for decades, their role in antigen recognition remains unclear. Guided by recent experiments, we built an anatomically informed stochastic model of MV scanning and compared with a topologically flat interface. We find that MV scanning modestly impacts antigen discrimination, yet it enables T-cells to balance the competing effects of maintaining sensitivity while conducting rapid APC surveillance. The model can reconcile discrepancies in observed MV lifetimes and demonstrates that observed area coverage fractions correspond to geometric packing limits. Our work suggests that MVs promote positive signaling outcomes despite anatomical constraints to close contact formation.