Integrin β1 Optimizes Diabetogenic T Cell Migration and Function in the Pancreas.

Gabriel Espinosa-Carrasco,Pierre Fontanaud,Javier Hernandez,Cécile Le Saout,Patrice Mollard,Marie Schaeffer,Aurélien Michau

doi:10.3389/fimmu.2018.01156

Abstract

T cell search behavior is dictated by their need to encounter their specific antigen to eliminate target cells. However, mechanisms controlling effector T cell motility are highly tissue-dependent. Specifically, how diabetogenic T cells encounter their target beta cells in dispersed islets throughout the pancreas (PA) during autoimmune diabetes remains unclear. Using intra-vital 2-photon microscopy in a mouse model of diabetes, we found that CXCR3 chemokine downregulated CD8+ T cell motility specifically within islets, promoting effector cell confinement to their target sites. By contrast, T cell velocity and directionality in the exocrine tissue were enhanced along blood vessels and extracellular matrix fibers. This guided migration implicated integrin-dependent interactions, since integrin blockade impaired exocrine T cell motility. In addition, integrin β1 blockade decreased CD4+ T cell effector phenotype specifically in the PA. Thus, we unveil an important role for integrins in the PA during autoimmune diabetes that may have important implications for the design of new therapies.

Highlights

Immune responses implicate sequential encounters between T cells and their specific antigen in different body compartments to ensure efficient T cell priming, activation, and antigen clearance [1, 2]
Mechanisms governing lymphocyte dynamics are intimately linked to the maintenance of T cell effector function [1]
Using 2-photon microscopy in vivo to visualize TCR transgenic HA-specific CD8+ and CD4+ T cells in the PA of mice expressing HA in beta cells, we found that both T cell types followed a super-diffusive Lévy-type mode of migration in the exocrine tissue without a preferred concerted orientation

Summary

Introduction

Immune responses implicate sequential encounters between T cells and their specific (or cognate) antigen in different body compartments to ensure efficient T cell priming, activation, and antigen clearance [1, 2]. Naïve T cells typically display a high velocity dependent on chemokines and interactions with dendritic cells [8, 9]. They migrate following a “Brownian” random walk intrinsically encoded [7, 10] and guided by a network of fibroblast reticular cells [11]. This ensures efficient sampling of a multitude of APCs [6] to

Methods

Results

Conclusion