Signal strength regulates antigen-mediated T-cell deceleration by distinct mechanisms to promote local exploration or arrest

Abstract

International audienceT lymphocytes are highly motile cells that decelerate upon antigen recognition. These cells can either completely stop or maintain a low level of motility, forming contacts referred to as synapses or kinapses, respectively. Whether similar or distinct molecular mechanisms regulate T-cell deceleration during synapses or kinapses is unclear. Here, we used microfabricated channels and intravital imaging to observe and manipulate T-cell kinapses and synapses. We report that high-affinity antigen induced a pronounced deceleration selectively dependent on Ca 2+ signals and actin-related protein 2/3 complex (Arp2/3) activity. In contrast, low-affinity antigens induced a switch of migration mode that promotes T-cell exploratory behavior, characterized by partial deceleration and frequent direction changes. This switch depended on T-cell receptor binding but was largely independent of downstream signaling. We propose that distinct mechanisms of T-cell deceleration can be triggered during antigenic recognition to favor local exploration and signal integration upon suboptimal stimulus and complete arrest on the best antigen-presenting cells

T cell migration, search strategies and mechanisms

“…This might especially be relevant for T cells that have a low affinity for their cognate peptide. Whereas high affinity cognate peptide induces arrest and stable T-APC interactions, weak-affinity peptides induce a switch of migration mode characterized by partial deceleration and frequent direction changes 43 . This would be expected to favor local exploitation so as to accumulate more TCR signaling.…”

Durable Interactions of T Cells With T Cell Receptor Stimuli in the Absence of a Stable Immunological Synapse

“…This inability is mainly a result of internal tissue movement and inherent limitations of 3D rendering. Synapses and kinapses have functional implications, with synapses being more efficient for effector functions (Beal et al, 2008;Huse et al, 2006) and kinapses allowing greater exploration of local networks (Moreau et al, 2015). However, it has been proposed that the polarized distribution of the motility apparatus along the plane of contact in the kinapse mode limits the durability of interaction (Davis, 2009;Dustin, 2007;Gunzer et al, 2000;Moreau and Bousso, 2014).…”

Function and regulation of the Arp2/3 complex during cell migration in diverse environments

“…As opposed to fibroblasts and neural progenitor cells, evidence shows that Arp2/3-mediated actin polymerization inhibits the migration of both dendritic and T cells, which will be discussed below [50,51]. However, a recent study of dendritic cells suggests that successful passage through narrow pores, which is determined by the physical constraints of the nucleus, is associated with an increase in actin polymerization around the nucleus as it reaches the point of constriction [52].…”

“…These contradictions may be due to experimental differences in migratory environments. Similarly to DCs, Arp2/3 activity inhibits T cell migration to promote synapse formation upon high-affinity antigen binding, but is not required for the fast motility of T cells that are unbound by antigen [50]. Homeostasis between Arp2/3- and formin-based polymerization in fission yeast is controlled by competition for actin monomers, ensuring the proper assembly of the contractile ring and endocytic actin patches [96].…”