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Sci. Signal., 27 November 2012
Vol. 5, Issue 252, p. ra87
[DOI: 10.1126/scisignal.2003365]

RESEARCH ARTICLES

Lack of the Phosphatase PTPN22 Increases Adhesion of Murine Regulatory T Cells to Improve Their Immunosuppressive Function

Rebecca J. Brownlie1, Lisa A. Miosge2*, Demetrios Vassilakos2{dagger}, Lena M. Svensson3,4, Andrew Cope3, and Rose Zamoyska1{ddagger}

1 Institute for Immunology and Infection Research, The University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK.
2 Molecular Immunology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
3 Academic Department of Rheumatology, Division of Immunology, Infection and Inflammatory Diseases, King’s College School of Medicine, Guy’s Campus, King’s College London, London SE1 1UL, UK.
4 Department of Experimental Medical Sciences, Immunology Section, Lund University, Lund SE-221 84, Sweden.

* Present address: Department of Immunology, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.

{dagger} Present address: Immunology Department, Epsom and St Helier University Hospitals NHS Trust, Surrey SM5 1AA, UK.

Abstract: The cytoplasmic phosphatase PTPN22 (protein tyrosine phosphatase nonreceptor type 22) plays a key role in regulating lymphocyte homeostasis, which ensures that the total number of lymphocytes in the periphery remains relatively constant. Mutations in PTPN22 confer an increased risk of developing autoimmune diseases; however, the precise function of PTPN22 and how mutations contribute to autoimmunity remain controversial. Loss-of-function mutations in PTPN22 are associated with increased numbers of effector T cells and autoreactive B cells in humans and mice; however, the complete absence of PTPN22 in mice does not result in spontaneous autoimmunity. We found that PTPN22 was a key regulator of regulatory T cell (Treg) function that fine-tuned the signaling of the T cell receptor and integrins. PTPN22–/– Tregs were more effective at immunosuppression than were wild-type Tregs, and they suppressed the activity of PTPN22–/– effector T cells, preventing autoimmunity. Compared to wild-type Tregs, PTPN22–/– Tregs produced increased amounts of the immunosuppressive cytokine interleukin-10 and had enhanced adhesive properties mediated by the integrin lymphocyte function–associated antigen-1, processes that are critical for Treg function. This previously undiscovered role of PTPN22 in regulating integrin signaling and Treg function suggests that PTPN22 may be a useful therapeutic target for manipulating Treg function in human disease.

{ddagger} To whom correspondence should be addressed. E-mail: rose.zamoyska{at}ed.ac.uk

Citation: R. J. Brownlie, L. A. Miosge, D. Vassilakos, L. M. Svensson, A. Cope, R. Zamoyska, Lack of the Phosphatase PTPN22 Increases Adhesion of Murine Regulatory T Cells to Improve Their Immunosuppressive Function. Sci. Signal. 5, ra87 (2012).

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