Binding of Rap1 and Riam to Talin1 Fine-Tune β2 Integrin Activity During Leukocyte Trafficking.

Thomas Bromberger,Markus Sperandio,Soo Jin Min-Weißenhorn,Jasmin Weber,Laura Mittmann,Sarah Klapproth,Ina Rohwedder,Markus Moser,Christoph Scheiermann,Robert Pick,Christoph A Reichel

doi:10.3389/fimmu.2021.702345

Abstract

β2 integrins mediate key processes during leukocyte trafficking. Upon leukocyte activation, the structurally bent β2 integrins change their conformation towards an extended, intermediate and eventually high affinity conformation, which mediate slow leukocyte rolling and firm arrest, respectively. Translocation of talin1 to integrin adhesion sites by interactions with the small GTPase Rap1 and the Rap1 effector Riam precede these processes. Using Rap1 binding mutant talin1 and Riam deficient mice we show a strong Riam-dependent T cell homing process to lymph nodes in adoptive transfer experiments and by intravital microscopy. Moreover, neutrophils from compound mutant mice exhibit strongly increased rolling velocities to inflamed cremaster muscle venules compared to single mutants. Using Hoxb8 cell derived neutrophils generated from the mutant mouse strains, we show that both pathways regulate leukocyte rolling and adhesion synergistically by inducing conformational changes of the β2 integrin ectodomain. Importantly, a simultaneous loss of both pathways results in a rolling phenotype similar to talin1 deficient neutrophils suggesting that β2 integrin regulation primarily occurs via these two pathways.

Highlights

Trafficking of neutrophils to sites of inflammation as well as lymphocyte homing to various destinations are fundamental processes of the immune system to defend the host against invaders
We recently showed that in fibroblasts the direct Rap1/talin pathway plays a central role in the regulation of integrin activation, whereas the talin/Riam interaction is irrelevant in these cells [23]
We wanted to address the question whether talin recruitment to the plasma membrane during b2 integrin activation can occur in the absence of Riam and whether the direct Rap1/talin pathway contributes

Summary

Introduction

Trafficking of neutrophils to sites of inflammation as well as lymphocyte homing to various destinations are fundamental processes of the immune system to defend the host against invaders. In particular members of the b2 integrin family, contribute to each of these processes upon activation, which may be triggered from surface proteins such as P-selectin glycoprotein ligand-1 (PSGL-1) or chemokine receptors [2,3,4]. While intermediate affinity integrin aLb2 support slow leukocyte rolling, transition to the high affinity conformation is required for firm adhesion [3]

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