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

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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Figure 1: B6 Qa-1(D227K) mice develop an autoimmune phenotype.
Figure 2: Germinal-centre formation and antibody response in B6 Qa-1 (wild-type) and B6 Qa-1(D227K) mice challenged with protein antigen or virus.
Figure 3: CD44 + ICOSL + CD8 + cell population targets T FH to block generation of high-affinity antibodies.
Figure 4: Mechanism of Qa-1-restricted suppression by CD8 T reg cells.

References

  1. Cantor, H. T-cell receptor crossreactivity and autoimmune disease. Adv. Immunol. 75, 209–233 (2000)

    CAS  Article  Google Scholar 

  2. Cantor, H. Reviving suppression? Nature Immunol. 5, 347–349 (2004)

    CAS  Article  Google Scholar 

  3. Josefowicz, S. Z. & Rudensky, A. Control of regulatory T cell lineage commitment and maintenance. Immunity 30, 616–625 (2009)

    CAS  Article  Google Scholar 

  4. Noble, A., Zhao, Z.-S. & Cantor, H. Suppression of immune responses by CD8 cells: II. Qa-1 on activated B-cells stimulates CD8 cell suppression of T helper 2 responses. J. Immunol. 160, 566–571 (1998)

    CAS  PubMed  Google Scholar 

  5. Jiang, H., Zhang, S.-L. & Pernis, B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science 256, 1213–1215 (1992)

    ADS  CAS  Article  Google Scholar 

  6. Hu, D. et al. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nature Immunol. 5, 516–523 (2004)

    CAS  Article  Google Scholar 

  7. Chen, W. et al. Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation. Proc. Natl Acad. Sci. USA 104, 20472–20477 (2007)

    ADS  CAS  Article  Google Scholar 

  8. Lu, L. & Cantor, H. Generation and regulation of CD8+ regulatory T cells. Cell Mol. Immunol. 5, 401–406 (2008)

    CAS  Article  Google Scholar 

  9. Lu, L., Kim, H. J., Werneck, M. B. & Cantor, H. Regulation of CD8+ regulatory T cells: Interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc. Natl Acad. Sci. USA 105, 19420–19425 (2008)

    ADS  CAS  Article  Google Scholar 

  10. Lu, L. et al. Regulation of activated CD4+ T cells by NK cells via the Qa-1–NKG2A inhibitory pathway. Immunity 26, 593–604 (2007)

    CAS  Article  Google Scholar 

  11. Bubier, J. A. et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc. Natl Acad. Sci. USA 106, 1518–1523 (2009)

    ADS  CAS  Article  Google Scholar 

  12. Linterman, M. A. et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561–576 (2009)

    CAS  Article  Google Scholar 

  13. Sangster, M. Y. et al. Analysis of the virus-specific and nonspecific B cell response to a persistent B-lymphotropic gammaherpesvirus. J. Immunol. 164, 1820–1828 (2000)

    CAS  Article  Google Scholar 

  14. Panoutsakopoulou, V. et al. Analysis of the relationship between viral infection and autoimmune disease. Immunity 15, 137–147 (2001)

    CAS  Article  Google Scholar 

  15. Hunziker, L. et al. Hypergammaglobulinemia and autoantibody induction mechanisms in viral infections. Nature Immunol. 4, 343–349 (2003)

    CAS  Article  Google Scholar 

  16. Mitchell, D. M., Ravkov, E. V. & Williams, M. A. Distinct roles for IL-2 and IL-15 in the differentiation and survival of CD8+ effector and memory T cells. J. Immunol. 184, 6719–6730 (2010)

    CAS  Article  Google Scholar 

  17. Zeng, R. et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med. 201, 139–148 (2005)

    ADS  CAS  Article  Google Scholar 

  18. Nurieva, R. I. et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138–149 (2008)

    CAS  Article  Google Scholar 

  19. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003)

    ADS  CAS  Article  Google Scholar 

  20. Yurasov, S. & Nussenzweig, M. C. Regulation of autoreactive antibodies. Curr. Opin. Rheumatol. 19, 421–426 (2007)

    CAS  Article  Google Scholar 

  21. Hao, Z. et al. Fas receptor expression in germinal-center B cells is essential for T and B lymphocyte homeostasis. Immunity 29, 615–627 (2008)

    CAS  Article  Google Scholar 

  22. Ray, S. K., Putterman, C. & Diamond, B. Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease. Proc. Natl Acad. Sci. USA 93, 2019–2024 (1996)

    ADS  CAS  Article  Google Scholar 

  23. Simpson, N. et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 62, 234–244 (2010)

    CAS  Article  Google Scholar 

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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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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 to Harvey Cantor.

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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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