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

Authors:

Claire Lacouture, Beatriz Chaves, Delphine Guipouy, Raïssa Houmadi, Valérie Duplan-Eche, Sophie Allart, Nicolas Destainville, Loïc Dupré

Keywords:

T-cell receptor, TCR, LFA-1, T-cell toxicity, ICAM-1, nanoclusters

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.

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