LFA-1 nanoclusters integrate TCR stimulation strength to tune T-cell cytotoxic activity

Claire Lacouture, Beatriz Chaves, Delphine Guipouy, Raïssa Houmadi, Valérie Duplan-Eche, Sophie Allart, Nicolas Destainville () and Loïc Dupré ()
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Claire Lacouture: Toulouse III Paul Sabatier University
Beatriz Chaves: Toulouse III Paul Sabatier University
Delphine Guipouy: Toulouse III Paul Sabatier University
Raïssa Houmadi: Toulouse III Paul Sabatier University
Valérie Duplan-Eche: Toulouse III Paul Sabatier University
Sophie Allart: Toulouse III Paul Sabatier University
Nicolas Destainville: Université de Toulouse, CNRS, UPS
Loïc Dupré: Toulouse III Paul Sabatier University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract T-cell cytotoxic function relies on the cooperation between the highly specific but poorly adhesive T-cell receptor (TCR) and the integrin LFA-1. How LFA-1-mediated adhesion may scale with TCR stimulation strength is ill-defined. Here, we show that LFA-1 conformation activation scales with TCR stimulation to calibrate human T-cell cytotoxicity. Super-resolution microscopy analysis reveals that >1000 LFA-1 nanoclusters provide a discretized platform at the immunological synapse to translate TCR engagement and density of the LFA-1 ligand ICAM-1 into graded adhesion. Indeed, the number of high-affinity conformation LFA-1 nanoclusters increases as a function of TCR triggering strength. Blockade of LFA-1 conformational activation impairs adhesion to target cells and killing. However, it occurs at a lower TCR stimulation threshold than lytic granule exocytosis implying that it licenses, rather than directly controls, the killing decision. We conclude that the organization of LFA-1 into nanoclusters provides a calibrated system to adjust T-cell killing to the antigen stimulation strength.

Date: 2024
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DOI: 10.1038/s41467-024-44688-3

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