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The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals

Nature Immunology volume 15, pages 875883 (2014) | Download Citation

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Abstract

T cells must be tolerant of self antigens to avoid autoimmunity but responsive to foreign antigens to provide protection against infection. We found that in both naive T cells and effector T cells, the tyrosine phosphatase PTPN22 limited signaling via the T cell antigen receptor (TCR) by weak agonists and self antigens while not impeding responses to strong agonist antigens. T cells lacking PTPN22 showed enhanced formation of conjugates with antigen-presenting cells pulsed with weak peptides, which led to activation of the T cells and their production of inflammatory cytokines. This effect was exacerbated under conditions of lymphopenia, with the formation of potent memory T cells in the absence of PTPN22. Our data address how loss-of-function PTPN22 alleles can lead to the population expansion of effector and/or memory T cells and a predisposition to human autoimmunity.

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Acknowledgements

We thank H. Shen (University of Pennsylvania) for the attenuated OVA-expressing L. monocytogenes strain with deletion of the actin assembly–inducing protein; D. Wright and C. Garcia for technical assistance, and P. Travers for reading the manuscript. Supported by the Wellcome Trust (096669 to R.Z., and 095831 for the Centre for Immunity, Infection and Evolution of the University of Edinburgh) and the Biotechnology and Biological Sciences Research Council (801148 to V.L.M.).

Author information

Author notes

    • Robert J Salmond
    •  & Rebecca J Brownlie

    These authors contributed equally to this work.

Affiliations

  1. Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, Ashworth Laboratories, The King's Buildings, University of Edinburgh, Edinburgh, UK.

    • Robert J Salmond
    • , Rebecca J Brownlie
    •  & Rose Zamoyska
  2. Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

    • Vicky L Morrison

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Contributions

R.J.S. designed and did most in vitro experiments; R.J.B. designed and did most in vivo experiments and in vitro analyses of the formation of T cell conjugates; V.L.M. designed and did analyses of adhesion under shear flow; R.Z. designed experiments and led the overall project; and R.J.S. and R.Z. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rose Zamoyska.

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DOI

https://doi.org/10.1038/ni.2958

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