Simulating CXCR5 Dynamics in Complex Tissue Microenvironments.

Jason Cosgrove,Jens V Stein,Jon Timmis,Kieran Alden,Mark C Coles

doi:10.3389/fimmu.2021.703088

Abstract

To effectively navigate complex tissue microenvironments, immune cells sense molecular concentration gradients using G-protein coupled receptors. However, due to the complexity of receptor activity, and the multimodal nature of chemokine gradients in vivo, chemokine receptor activity in situ is poorly understood. To address this issue, we apply a modelling and simulation approach that permits analysis of the spatiotemporal dynamics of CXCR5 expression within an in silico B-follicle with single-cell resolution. Using this approach, we show that that in silico B-cell scanning is robust to changes in receptor numbers and changes in individual kinetic rates of receptor activity, but sensitive to global perturbations where multiple parameters are altered simultaneously. Through multi-objective optimization analysis we find that the rapid modulation of CXCR5 activity through receptor binding, desensitization and recycling is required for optimal antigen scanning rates. From these analyses we predict that chemokine receptor signaling dynamics regulate migration in complex tissue microenvironments to a greater extent than the total numbers of receptors on the cell surface.

Highlights

Through interactions with non-hematopoietic stromal cells, B-cells generate tightly compartmentalized structures known as B-cell follicles within secondary lymphoid tissues
In this study we focus on CXCR5 the cognate receptor for CXCL13, a chemokine produced by stromal fibroblasts that is essential for follicle formation and maintenance [4,5,6]
CXCL13Sim is a 3D hybrid multiscale model developed using the CoSMoS (Complex System Modelling and Simulation) process, a framework to guide the modelling and analysis of complex systems. In this scheme B cells are modelled as agents that adjust their behaviors with respect to vector and ordinary differential equationbased calculations adapted from a published scheme [50] that explicitly accounts for gradient detection and the dynamics of G-protein coupled receptors (GPCRs) expression on the cell surface (Figures 1A, B)

Summary

Introduction

Through interactions with non-hematopoietic stromal cells, B-cells generate tightly compartmentalized structures known as B-cell follicles within secondary lymphoid tissues. The precise spatial positioning of B cells within the follicular niche is regulated by G-protein coupled receptors (GPCRs) that bind signaling lipids and chemokines inducing directed migration along a concentration gradient [2, 3]. In this study we focus on CXCR5 the cognate receptor for CXCL13, a chemokine produced by stromal fibroblasts that is essential for follicle formation and maintenance [4,5,6]. CXCR5 deficient B cells display aberrant migratory behaviors within lymph nodes, a phenotype associated with impaired homing to follicles [4, 7]. Western blotting of pooled lymph nodes, in vitro migration assays, and measurements of the dissociation constant of CXCR5-CXCL13 suggest that the follicular

Objectives

Methods

Results

Conclusion