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Universal recording of immune cell interactions in vivo.

ABSTRACT: Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function¹. To study these 'kiss-and-run' interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts)², an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4⁺ T helper cells and antigen-presenting cells, however. Here we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8⁺ T cells by dendritic cells, reveal the steady-state cellular partners of regulatory T cells and identify germinal centre-resident T follicular helper cells on the basis of their ability to interact cognately with germinal centre B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalogue of the immune populations that physically interact with intestinal epithelial cells at the steady state and profile the evolution of the interactome of lymphocytic choriomeningitis virus-specific CD8⁺ T cells in multiple organs following systemic infection. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems.

SUBMITTER: Nakandakari-Higa S

PROVIDER: S-EPMC11078586 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Universal recording of immune cell interactions in vivo.

Nakandakari-Higa Sandra S Walker Sarah S Canesso Maria C C MCC van der Heide Verena V Chudnovskiy Aleksey A Kim Dong-Yoon DY Jacobsen Johanne T JT Parsa Roham R Bilanovic Jana J Parigi S Martina SM Fiedorczuk Karol K Fuchs Elaine E Bilate Angelina M AM Pasqual Giulia G Mucida Daniel D Kamphorst Alice O AO Pritykin Yuri Y Victora Gabriel D GD

Nature 20240306 8003

Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function<sup>1</sup>. To study these 'kiss-and-run' interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts)<sup>2</sup>, an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPS ...[more]

PMID: 38448581

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Project description:Chimeric antigen receptor (CAR) T cells have shown great success in the treatment of CD19+ hematological malignancies, leading to their recent approval by the FDA as a new cancer treatment modality. However, their broad use is limited since a CAR targets a single tumor associated antigen (TAA), which is not effective against tumors with heterogeneous TAA expression or emerging antigen loss variants. Further, stably engineered CAR T cells can continually and uncontrollably proliferate and activate in response to antigen, potentially causing fatal on-target off-tumor toxicity, cytokine release syndrome, or neurotoxicity without a method of control or elimination. To address these issues, our lab and others have developed various universal immune receptors (UIRs) that allow for targeting of multiple TAAs by T cells expressing a single receptor. UIRs function through the binding of an extracellular adapter domain which acts as a bridge between intracellular T cell signaling domains and a soluble tumor antigen targeting ligand (TL). The dissociation of TAA targeting and T cell signaling confers many advantages over standard CAR therapy, such as dose control of T cell effector function, the ability to simultaneously or sequentially target multiple TAAs, and control of immunologic synapse geometry. There are currently four unique UIR platform types: ADCC-mediating Fc-binding immune receptors, bispecific protein engaging immune receptors, natural binding partner immune receptors, and anti-tag CARs. These UIRs all allow for potential benefits over standard CARs, but also bring unique engineering challenges that will have to be addressed to achieve maximal efficacy and safety in the clinic. Still, UIRs present an exciting new avenue for adoptive T cell transfer therapies and could lead to their expanded use in areas which current CAR therapies have failed. Here we review the development of each UIR platform and their unique functional benefits, and detail the potential hurdles that may need to be overcome for continued clinical translation.

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Universal recording of immune cell interactions in vivo.

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Universal recording of immune cell interactions in vivo.

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