2. Academic Validation
  3. Submicrometre sampling of living cells by macrophages

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

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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