Light-inducible T cell engagers trigger, tune, and shape the activation of primary T cells
Morgane Jaeger, Amandine Anastasio, Léa Chamy, Sophie Brustlein, Renaud Vincentelli, Fabien Durbesson, Julien P. Gigan, Morgane Thépaut, Rémy Char, Maud Boussand, Mathias Lechelon, Rafael J. Argüello, Didier Marguet, Hai‐Tao He, Rémi Lasserre
Abstract
To mount appropriate responses, T cells integrate complex sequences of receptor stimuli perceived during transient interactions with antigen-presenting cells. Although it has been hypothesized that the dynamics of these interactions influence the outcome of T cell activation, methodological limitations have hindered its formal demonstration. Here, we have engineered the Light-inducible T cell engager (LiTE) system, a recombinant optogenetics-based molecular tool targeting the T cell receptor (TCR). The LiTE system constitutes a reversible molecular switch displaying exquisite reactivity. As proof of concept, we dissect how specific temporal patterns of TCR stimulation shape T cell activation. We established that CD4 + T cells respond to intermittent TCR stimulation more efficiently than their CD8 + T cells counterparts and provide evidence that distinct sequences of TCR stimulation encode different cytokine programs. Finally, we show that the LiTE system could be exploited to create light-activated bispecific T cell engagers and manipulate tumor cell killing. Overall, the LiTE system provides opportunities to understand how T cells integrate TCR stimulations and to trigger T cell cytotoxicity with high spatiotemporal control.