Submicrometre sampling of living cells by macrophages

  • Nature. 2026 Jun;654(8118):495-503. doi: 10.1038/s41586-026-10435-5.
Amy C Fan  #  1 ,  Rukman R Thota  #  2  3 ,  Nina Serwas  #  2  4 ,  Vivasvan S Vykunta  2  3  5 ,  Kyle Marchuk  6 ,  Megan K Ruhland  2  7 ,  Lauren Liu  2 ,  Grace Johnson  2 ,  Austin Edwards  6 ,  Matthew F Krummel  8
Affiliations
  • 1. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 2. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • 3. Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • 4. Arcus Biosciences, Hayward, CA, USA.
  • 5. Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA.
  • 6. Parnassus Advanced Light Microscopy CoLab, University of California, San Francisco, San Francisco, CA, USA.
  • 7. Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
  • 8. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • # Contributed equally.
PMID: 42056510 DOI: 10.1038/s41586-026-10435-5
Abstract

An effective immune system must sample and develop healthy self-identity to prevent autoimmunity and to discern pathogenic insults1-3. Self-proteins are presented to T cells in the thymus during immune cell development2,3 and must be presented throughout the body to maintain regulatory T cell populations4-6 and to provide tonic signals to sustain conventional T cells over time7-9. Observations of continuous Apoptosis in some organs together with the ingestion of that material by myeloid populations has led to a conventional understanding of ongoing cell death as a major source of self-antigens10. Here we used a series of companion imaging and vesicular labelling technologies to reveal an alternative process undertaken by macrophages that results in non-destructive, direct sampling of living cells. This process requires cell-cell contact, does not require Caspase activation and occurs via trogocytosis-like stretching of the target cell into the macrophage, which leads to the generation of submicrometre-sized vesicles that contain cytoplasm. Using a high-dimensional flow-based method for labelling vesicles, we demonstrate that live-sampled material is distinctly processed and is poorly subjected to fusion with lysosomes. The material also produces differential effects on the presentation of antigen to CD4 T cells compared with CD8 T cells. Disruption of this trafficking by redirecting antigen to the lysosome significantly reduced the associated macrophage-mediated priming of CD8 T cells. These results demonstrate an important and substantial sampling of living cells by the immune system, with clear consequences for maintaining the border of immunity.

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