Cytotoxic T cells swarm by homotypic chemokine signalling.

Feyza Colakoglu,Maté Biro,Laura F Dagley ,Mark Read ,Jessica K Mazalo,James Cremasco,Fabio Luciani,Jorge Luis Galeano Niño,Victoria Prior,Ku‐Lung Hsu ,Simone Rizzetto,Jerzy Zieba,Szun S Tay ,Daryan Kempe,Andrew I Webb ,David R Nisbet ,Jack D Hywood ,Belinda Kramer,Geraldine M O’neill ,Sophie V Pageon ,Matt Govendir ,Richard J Williams ,Gregory Rice

doi:10.7554/elife.56554

Abstract

Cytotoxic T lymphocytes (CTLs) are thought to arrive at target sites either via random search or following signals by other leukocytes. Here, we reveal independent emergent behaviour in CTL populations attacking tumour masses. Primary murine CTLs coordinate their migration in a process reminiscent of the swarming observed in neutrophils. CTLs engaging cognate targets accelerate the recruitment of distant T cells through long-range homotypic signalling, in part mediated via the diffusion of chemokines CCL3 and CCL4. Newly arriving CTLs augment the chemotactic signal, further accelerating mass recruitment in a positive feedback loop. Activated effector human T cells and chimeric antigen receptor (CAR) T cells similarly employ intra-population signalling to drive rapid convergence. Thus, CTLs recognising a cognate target can induce a localised mass response by amplifying the direct recruitment of additional T cells independently of other leukocytes.

Highlights

Cytotoxic T lymphocytes (CTLs) constitutively migrate as single cells in search of infected or malignant cells (Weninger et al, 2014)
Ccr5-/- CTLs cleared tumours with comparable efficacy to WT CTLs (Figure 5—figure supplement 2G). These results indicate that sustained release of CCL3 and CCL4 is sufficient to promote CCR5-dependent homing into tumours in vivo, and that the presence of tumour-reactive CTLs in a tumour promotes the recruitment of distant CCR5+ CTLs
Our data reveal that CTLs engaging targets employ homotypic signalling via secretion of the chemokines CCL3 and CCL4 to accelerate the direct recruitment of distant T cells

Summary

Introduction

Cytotoxic T lymphocytes (CTLs) constitutively migrate as single cells in search of infected or malignant cells (Weninger et al, 2014). The methods used to map the movement of these killer cells have made it difficult to determine how populations of CTLs coordinate their behaviour independently of other cells in the immune system To overcome this barrier, Galeano Nin~o, Pageon, Tay et al employed a three-dimensional model known as a tumouroid embedded in a matrix of proteins, which mimics the tissue environment of a real tumour in the laboratory. The experiments showed that when a CTL identifies a tumour cell, it releases chemical signals known as chemokines, which attract other CTLs and recruit them to the target site. Further experiments and computer simulations revealed that as the number of CTLs arriving at the target site increases, this amplifies the chemokine signal being secreted, resulting in more and more CTLs being attracted to the tumour. Our findings provide insights into how CTL populations amplify directed recruitment to an effector site independently of other leukocytes

Results

C Cognate versus non-cognate cells

Discussion

Materials and methods