New weapon identified in arsenal against disease

Scientists at the Kennedy Institute of Rheumatology in the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences have discovered a new way for T cells to attack cells infected by viruses or deranged by cancer.

Published online by the journal

Science

on Thursday 7 May 2020, the new research from the Dustin Group describes the structure and composition of supramolecular attack particles (SMAPs) and their role in killing targeted cells.

Cytotoxic T lymphocytes (CTLs) are essential components in the immune response against viruses and cancer. CTLs are known to recognise infected or damaged cells and release soluble protein molecules, which create perforations in the membrane of the targeted cell. These holes allow toxic enzymes to enter and initiate a self-destruct program, killing the targeted cell (cytotoxicity).

The new study reveals a complementary mechanism of cytotoxicity in the CTLs. The team identified SMAPs, ~120 nm diameter protein particles released by CTLs to kill other cells, for example, if virally infected or cancerous. SMAPs have a core of cytotoxic proteins surrounded by a glycoprotein shell.

The core-shell structure was demonstrated in collaboration with the B24 beam line at the Diamond Light Source at the Harwell Science and Innovation Campus using cryo-soft-x-ray tomography. “Using this national resource we were able to determine the physical nature of the particles. This confirmed and extended our observations with super-resolution fluorescence microscopy,” said Stefan Balint, Postdoctoral research assistant in molecular immunology who spearheaded the work at the Kennedy Institute.

The core-shell structure of the SMAPs allowed for the whole unit to be released from the CTL and 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,” said 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.”

A better understanding of SMAPs could be useful to develop new strategies to reinforce CTL activity in anti-viral immunity, cancer immunotherapy, regulation of the immune response and many other settings. 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 tumours and other patient specific treatments,” added Mike Dustin.

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Clues to SMAP biology and structure were provided by collaborators in the Target Discovery Institute at Oxford and at the University of Toulouse, France.

The European Commission, Wellcome Trust, Kennedy Trust for Rheumatology Research, Versus Arthritis, STFC, TOUCAN and Ligue Nationale contre le Cancer funded the work.