Spatial dynamic modelling to understand how dendritic cell clustering affects T cell activation

TL;DR

This paper introduces a novel spatially dynamic model combining agent-based and PDE approaches to analyze how dendritic cell clustering influences T cell activation within lymph nodes, with implications for cancer immunology.

Contribution

It develops a new probabilistic agent-based model and PDE framework to analytically study the effects of dendritic cell clustering on T cell activation, providing insights into spatial immune dynamics.

Findings

Intermediate dendritic cell clustering optimizes T cell activation.

Higher clustering levels lead to greater heterogeneity in T cell stimulation.

T cells benefit most from clustering when they have an intermediate stimulation uptake.

Abstract

The coordination of the immune system and its components is essential for the body to maintain a healthy status. Recent clinical studies show that breast cancer patients with high Dendritic cell clustering in tumour draining lymph nodes have improved survival outcomes, compared to those with a lower degree of clustering. These results suggest that a specific form of Dendritic cell clustering promotes T cell activation. However, the mechanistic effects of this spatial organisation is unclear. We develop a spatially dynamic model of T cells interacting with Dendritic cells within the lymph node. We present a novel probabilistic agent-based model (ABM) of T cells, and use it to derive the deterministic, phenotypically structured partial differential equation (PS-PDE) of T cell activation and motion. Using the PS-PDE, we derive analytic approximations of the expected T cell stimulation distribution, based on the topology and level of clustering of a given Dendritic cell population. Our analytic approximation enables us to identify T cell characteristics that benefit most from Dendritic cell clustering, to result in an enhanced stimulation distribution. We also perform a sensitivity analysis with our models to identify T cell characteristics that result in desirable T cell activation characteristics, such as rapid T cell activation, and robust heterogeneous T cell activation. Our key findings show that T cells with an intermediate level of stimulation uptake benefit most from higher levels of Dendritic cell clustering, activating with a comparable or greater abundance, and greater heterogeneity, when compared to T cells of a similar characteristic but with a lower level of Dendritic cell clustering.