Inhibition of follicular T-helper cells by CD8+ regulatory T cells is essential for self tolerance (original) (raw)

Nature volume 467, pages 328–332 (2010)Cite this article

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Abstract

The ability to produce vigorous immune responses that spare self tissues and organs depends on the elimination of autoreactive T and B cells. However, purging of immature and mature self-reactive T and B cells is incomplete and may also require the involvement of cells programmed to suppress immune responses1. Regulatory T cells (Treg) belonging to the CD4+ T-cell subset may have a role in preventing untoward inflammatory responses, but T-cell subsets programmed to inhibit the development of autoantibody formation and systemic-lupus-erythematosus-like disease have not yet been defined2. Here we delineate a CD8+ regulatory T-cell lineage that is essential for the maintenance of self tolerance and prevention of murine autoimmune disease. Genetic disruption of the inhibitory interaction between these CD8+ T cells and their target Qa-1+ follicular T-helper cells results in the development of a lethal systemic-lupus-erythematosus-like autoimmune disease. These findings define a sublineage of CD8 T cells programmed to suppress rather than activate immunity that represents an essential regulatory element of the immune response and a guarantor of self tolerance.

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Acknowledgements

We thank R. Bronson (DF/HCC Rodent Histopathology Core) for histology analysis, R. Gelman and J. Yang for help with statistical analyses, C. Daniel and T. Kreslavsky for cytometry support and critical discussions, M. Iannacone and U. von Andrian for LCMV, X. Wang for technical assistance, M. Call, D. A. Alvarez Arias, T. Kadakia and A. Angel for manuscript and figure preparation. This work was supported in part by NIH Research Grant AI 037562, the Lupus Research Institute and a gift from the Schecter Research Foundation to H.C.; National Research Service Award Fellowships (DFCI/NCI T32 CA070083) to H.-J.K. and (HSPH/NCI T32 CA009382) to X.T.; and a Belgian American Educational Foundation Fellowship to B.V.

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Authors and Affiliations

  1. Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, USA
    Hye-Jung Kim, Bert Verbinnen, Xiaolei Tang & Harvey Cantor
  2. Department of Pathology, Harvard Medical School, 44 Binney Street, Boston, 02115, Massachusetts, USA
    Hye-Jung Kim, Bert Verbinnen, Xiaolei Tang & Harvey Cantor
  3. Institute of Immunology, Zhejiang University, School of Medicine, Hangzhou, 310058, China
    Linrong Lu

Authors

  1. Hye-Jung Kim
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  2. Bert Verbinnen
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  3. Xiaolei Tang
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  4. Linrong Lu
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  5. Harvey Cantor
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Contributions

H.-J.K. and H.C. conceived and planned experiments; H.-J.K., B.V., X.T. and L.L. performed experiments; H.-J.K. and H.C. analysed data and wrote the paper.

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Correspondence toHarvey Cantor.

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The authors declare no competing financial interests.

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Kim, HJ., Verbinnen, B., Tang, X. et al. Inhibition of follicular T-helper cells by CD8+ regulatory T cells is essential for self tolerance.Nature 467, 328–332 (2010). https://doi.org/10.1038/nature09370

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Editorial Summary

Role for CD8+ regulatory T cells in self-tolerance

Analysis of the immune system has defined a subset of CD4+ T cells, termed CD4+ Treg, that can inhibit excessive inflammatory immune responses. However, no T cells genetically programmed to inhibit autoantibody formation and systemic-lupus-erythematosus-like disease have so far been defined. A mechanism fitting that description has now been identified in mice. A subset of CD8+ T cells (CD8+ Treg) is shown to prevent autoantibody formation and maintain self-tolerance in a process that involves recognition of Qa-1 peptide ligands expressed at the surface of follicular helper T cells. A detailed understanding of this aspect of immune-system regulation could lead to new approaches for the treatment of systemic lupus erythematosus and other autoimmune disorders.