Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Cytotoxic T lymphocytes (CTLs) are crucial for eliminating infected and cancerous cells.
• The precise mechanisms by which CTLs deliver cytotoxic payloads remain an active area of research.

Purpose of the Study:

• To investigate the nature and function of cytotoxic multiprotein complexes released by CTLs.
• To identify the molecular components and structural organization of these extracellular cytotoxic entities.

Main Methods:

• Mass spectrometry and immunochemical analysis were used to identify SMAP components.
• CRISPR editing was employed to assess the functional role of identified components.
• Direct stochastic optical reconstruction microscopy (dSTORM) and cryo-soft X-ray tomography were utilized for structural analysis.

Main Results:

• Supramolecular attack particles (SMAPs), autonomously cytotoxic multiprotein complexes, were detected being transferred from CTLs to target cells.
• A carboxyl-terminal fragment of thrombospondin-1 was identified as a key component of SMAPs, contributing to target cell killing.
• SMAPs possess a distinct structure with a cytotoxic core and a thrombospondin-1 shell (~120 nm diameter) and are stored in multicore granules.

Conclusions:

• SMAPs represent novel, autonomous extracellular entities capable of delivering cytotoxic cargo.
• Thrombospondin-1 plays a critical role in the structure and function of SMAPs.
• These findings reveal a new mechanism for CTL-mediated cytotoxicity and suggest potential therapeutic applications.