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Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation

Nature Medicine volume 13, pages 423431 (2007) | Download Citation

Abstract

Treatment with ex vivo–generated regulatory T cells (T-reg) has been regarded as a potentially attractive therapeutic approach for autoimmune diseases. However, the dynamics and function of T-reg in autoimmunity are not well understood. Thus, we developed Foxp3gfp knock-in (Foxp3gfp.KI) mice and myelin oligodendrocyte glycoprotein (MOG)35–55/IAb (MHC class II) tetramers to track autoantigen-specific effector T cells (T-eff) and T-reg in vivo during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. MOG tetramer–reactive, Foxp3+ T-reg expanded in the peripheral lymphoid compartment and readily accumulated in the central nervous system (CNS), but did not prevent the onset of disease. Foxp3+ T cells isolated from the CNS were effective in suppressing naive MOG-specific T cells, but failed to control CNS-derived encephalitogenic T-eff that secreted interleukin (IL)-6 and tumor necrosis factor (TNF). Our data suggest that in order for CD4+Foxp3+ T-reg to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation.

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Acknowledgements

We thank D. Kozoriz for performing the cell sorting. MOG35–55 peptide was provided by D. Teplow (David Geffen School of Medicine, University of California Los Angeles). This work was supported by the National Multiple Sclerosis Society (RG-2571-D-9 to V.K.K. and RG-3882-A-1 to M.O.), the US National Institutes of Health (1R01NS045937-01, 2R01NS35685-06, 2R37NS30843-11, 1R01A144880-03, 2P01A139671-07, 1P01NS38037-04 and 1R01NS046414) and the Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard Medical School. T.K. is supported by the Deutsche Forschungsgemeinschaft (KO 2964/1-1). V.K.K. is a recipient of the Javits Neuroscience Investigator Award from the US National Institutes of Health.

Author information

Author notes

    • Mohamed Oukka
    •  & Vijay K Kuchroo

    These authors contributed equally to this work.

Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Thomas Korn
    • , Jayagopala Reddy
    • , Estelle Bettelli
    • , Amit Awasthi
    • , Mohamed Oukka
    •  & Vijay K Kuchroo
  2. Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Wenda Gao
    •  & Terry B Strom
  3. Malaghan Institute of Medical Research, P.O. Box 7060, Wellington South, New Zealand.

    • Troels R Petersen
    •  & B Thomas Bäckström
  4. Laboratory Service, Veterans Affairs Health Care System, Palo Alto, California 94304, and Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Raymond A Sobel
  5. Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Kai W Wucherpfennig

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Contributions

T.K. conducted all experiments, prepared the figures and drafted the manuscript; J.R. generated the MOG tetramers; W.G. and M.O. generated the Foxp3gfp.KI mice; E.B., T.R.P. and B.T.B. helped in preparing the MOG35–55/IAb constructs; A.A. helped in generating the Foxp3gfp.KI and SJL Foxp3gfp.KI. mice; R.A.S. performed the immunohistological analyses; K.W.W. supervised the generation of the MOG35–55/IAb constructs; T.B.S. and M.O. supervised the project: V.K.K. initiated and supervised the project and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mohamed Oukka or Vijay K Kuchroo.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    T-reg population dynamics during EAE.

  2. 2.

    Supplementary Fig. 2

    Mononuclear cells were isolated from lymph nodes (LN), spleen (SPL), and CNS at different stages of EAE followed by ex vivo-stimulation with PMA/ionomycin and intracellular cytokine staining.

  3. 3.

    Supplementary Fig. 3

    Natural Foxp3+ T-reg proliferate in vivo.

  4. 4.

    Supplementary Fig. 4

    T-eff and T-reg dynamics and function during the first disease episode in PLP139-151-induced EAE.

  5. 5.

    Supplementary Methods

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DOI

https://doi.org/10.1038/nm1564

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