Article | Published:

A septin requirement differentiates autonomous and contact-facilitated T cell proliferation

Nature Immunology volume 17, pages 315322 (2016) | Download Citation

Abstract

T cell proliferation is initiated by T cell antigen receptor (TCR) triggering, soluble growth factors or both. In characterizing T cells lacking the septin cytoskeleton, we found that successful cell division has discrete septin-dependent and septin-independent pathways. Septin-deficient T cells failed to complete cytokinesis when prompted by pharmacological activation or cytokines. In contrast, cell division was not dependent on septins when cell-cell contacts, such as those with antigen-presenting cells, provided a niche. This septin-independent pathway was mediated by phosphatidylinositol-3-OH kinase activation through a combination of integrins and costimulatory signals. We were able to differentiate between cytokine- and antigen-driven expansion in vivo and thus show that targeting septins has strong potential to moderate detrimental bystander or homeostatic cytokine-driven proliferation without influencing expansion driven by conventional antigen-presentation.

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Acknowledgements

We thank the Biological Imaging Development Center personnel (UCSF) for technical assistance with imaging, J. Roose and O. Ksionda (UCSF) for reagents and helpful discussion, E. Palmer (University Hospital Basel and University of Basel) and D. Zehn (Swiss Vaccine Research Institute and Lausanne University Hospital) for reagents, and M. Kuhns (University of Arizona College of Medicine) for critical reading of the manuscript. Supported by the US National Institutes of Health (R01AI52116 to (M.F.K).

Author information

Author notes

    • Julia K Gilden

    Present address: Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

Affiliations

  1. Department of Pathology, University of California, San Francisco, San Francisco, California, USA.

    • Adriana M Mujal
    • , Julia K Gilden
    • , Audrey Gérard
    •  & Matthew F Krummel
  2. Division of Biological Sciences, Nagoya University Graduate School of Science, Nagoya, Japan.

    • Makoto Kinoshita

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Contributions

A.M.M. and M.F.K. designed the experiments for all primary text figures; A.M.M. did experiments; J.K.G. performed and helped with experiments related to initial characterization of Sept7cKO mice; A.G. contributed to experimental design and analysis; M.K. provided the Sept7flox/flox mice and consulted on experiments; A.M.M. and M.F.K. wrote and revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Matthew F Krummel.

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DOI

https://doi.org/10.1038/ni.3330