Cytotoxic T lymphocytes (CTLs) are versatile killers. When they detect a target—a cell infected by a virus or deranged by cancer—they can release soluble proteins that punch holes in a targeted cell’s membrane, exposing the targeted cell’s innards to toxic enzymes that cause it to self-destruct. But that’s not all, report scientists based at the University of Oxford. According to these scientists, CTLs may release supramolecular attack particles (SMAPs), which may attach to (and destroy) a target cell straightaway, or linger in the intracellular environment autonomously. The upshot is that SMAPS—glycoprotein shells packed with “explosive” cytotoxic proteins—may act as hand grenades or land mines.

That CTLs may act as minelayers is a new observation, one that became possible through a collaboration between the University of Oxford scientists and researchers at the Harwell Science and Innovation Campus who operate the B24 beamline at the Diamond Light Source. Using cryo-soft X-ray tomography, the collaborators probed the core-shell physical nature of SMAPs and determined that SMAPs, upon release from CTLs, remain stable and retain cytotoxic potential. That is, SMAPs may lie in wait, ready to detonate. But what is the trigger?

SMAP structure and the SMAP triggering mechanism were addressed in a paper (“Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells”) that appeared in the journal Science. The paper not only described shell-core SMAP granules, it also presented a working model for SMAP function. SMAP granules, the paper explained, may act as autonomous killing entities with innate targeting through thrombospondin-1, a shell component.

“Mass spectrometry, immunochemical analysis, and CRISPR editing identified a C-terminal fragment of thrombospondin-1 as an unexpected SMAP component that contributed to target killing,” the article’s authors wrote. “Direct stochastic optical reconstruction microscopy resolved a cytotoxic core surrounded by a thrombospondin-1 shell of ~120 nm diameter. Cryo-soft X-ray tomography analysis revealed that SMAPs had a carbon-dense shell and were stored in multicore granules.”

Cryo-soft X-ray tomography projection of a CD8+ T cell interacting with a carbon-coated EM grid containing ICAM-1 and anti-CD3e (left). SMAPs (middle) can be observed within the multicore granules inside the cell. dSTORM images of an individual SMAP positive for perforin (green), WGA (orange), and granzyme B (magenta) released by CD8+ T cells (right). [Kennedy Institute of Rheumatology, University of Oxford]
The Diamond Light Source allowed the scientists to determine the physical nature of the particles, noted Stefan Balint, PhD, a co-author of the current paper and a postdoctoral research assistant in molecular immunology at the University of Oxford’s Kennedy Institute of Rheumatology. “This work confirmed and extended our observations with super-resolution fluorescence microscopy,” he added.

The study determined that the core-shell structure of the SMAPs allows the SMAPs to be released from a CTL whole, whereupon the SMAPS may immediately attach to a target to kill it. The study also showed the potential for SMAPs to exist independently and autonomously from the CTL. “The CTL could leave it in the environment like a land mine,” emphasized Mike Dustin, director of research of the Kennedy Institute. “If the cytotoxic proteins are like bullets in the CTL’s arsenal then the SMAP is a bomb.”

The explosive findings may be followed by a barrage of targeted research. For example, a better understanding of SMAPs could encourage developers to use CTL activity to bolster antiviral immunity, cancer immunotherapy, regulation of the immune response, and other forms of defense. SMAPs have been discovered in CTL and natural killer cells, but proteinaceous particles with core-shell structures may have wider implications for physiology and disease. “We are particularly excited about the potential for engineering SMAPs to very specific targeting of tumors and other patient-specific treatments,” declared Dustin.

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