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Involvement of inhibitory NKRs in the survival of a subset of memory-phenotype CD8+ T cells

Nature Immunology volume 2, pages 430–435 (2001)Cite this article

An Erratum to this article was published on 01 July 2001

Abstract

Inhibitory natural killer receptors (NKRs) such as killer cell immunoglobulin-like receptors (KIRs) in humans and Ly49 molecules in mice are expressed on NK cells and recognize multiple major histocompatibility (MHC) class I proteins. In humans and mice, a subset of CD8+ T cells also expresses NKRs and harbors a memory phenotype. Using mice that are transgenic for KIR2DL3 and its cognate HLA-Cw3 ligand, we show that engagement of inhibitory NKRs selectively drives the in vivo accumulation of a subset of memory-phenotype CD8+ T cells that express the β chain of the interleukin 2 receptor. In vitro, recognition of MHC class I molecules by inhibitory NKRs on T cells down-regulated activation-induced cell death. These results unveil an MHC class I–dependent pathway that promotes the survival of a subset of memory-phenotype CD8+ T cells and also reveal an unexpected biological function for inhibitory NKRs on T cells.

NOTE: Incorrect reference numbering appeared in both the original print and web versions of this article. The instances of these errors are marked by asterisks (*) in the online version. The errors are: (i) Ref. 28 was printed incorrectly and should be Ref. 31; (ii) Ref. 29 was printed incorrectly and should be Ref. 32; (iii) References 28–32 should read as follows: 28. Zajac, A. J. et al. Impaired Anti-viral T cell responses due to expression of the LY49A inhibitory receptor. J. Immunol. 163, 5526-5534 (1999). 29. Pauza, M. et al. Transgenic expression of Ly-49A in thymocytes alters repertoire selection. J. Immunol. 164, 884-892 (2000). 30. Fahlen, L. et al. Ly49A expression on T cells alters T cell selection. Int. Immunol. 12, 215-222 (2000). 31. Marti, F. et al. LCK-phosphorylated human killer cell-inhibitory receptors recruit and activate phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA. 95, 11810-11815 (1998). 32. Bieganowska, K. et al. Direct analysis of viral-specific CD8+ T cells with soluble HLA-A2/Tax11-19 tetramer complexes in patients with human T cell lymphotropic virus-associated myelopathy. J. Immunol. 162, 1765-1771 (1999). We apologize for any confusion this may have caused. The most updated version of the article is available in PDF format.

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Figure 1: Characterization of CD8+ T cells isolated from KIR Tg and KIR-HLA Tg mice.
Figure 2: Mixed bone marrow chimeras.
Figure 3: Cycling pattern of CD8+ T cell subsets in control and KIR-HLA Tg mice.
Figure 4: CD8+ T cell phenotype in naïve KIR-HLA-P14 Tg mice.
Figure 5: Immunization of control and KIR-HLA Tg mice with P815.
Figure 6: Infection of control and KIR-HLA Tg mice with Ad5Ts125 virus.
Figure 7: Capacity of KIR+ and KIR− T cells to proliferate and survive in vitro.

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References

  1. Lanier, L. L. NK Cell Receptors. Ann. Rev. Immunol. 16, 359–393 (1998).

    Article  CAS  Google Scholar 

  2. Long, E. O. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 17, 875–904 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Tomasello, E., Bléry, M., Vély, F. & Vivier, E. Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells. Semin. Immunol. 12, 139–147 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Colonna, M. et al. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J. Exp. Med. 186, 1809–1818 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Borges, L., Fanger, N. & Cosman, D. Interactions of LIRs, a family of immunoreceptors expressed in myeloid and lymphoid cells, with viral and cellular MHC class I antigens. Curr. Top. Microbiol. Immunol. 244, 123–136 (1999).

    CAS  PubMed  Google Scholar 

  6. Chapman, T. L., Heikeman, A. P. & Bjorkman, P. J. The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 11, 603–613 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Mingari, M. C., Moretta, A. & Moretta, L. Regulation of KIR expression in human T cells: a safety mechanism that may impair protective T-cell responses. Immunol. Today 19, 153–157 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Speiser, D. E. et al. In vivo expression of natural killer cell inhibitory receptors by human melanoma-specific cytolytic T lymphocytes. J. Exp. Med. 190, 775–782 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Anfossi, N., Pascal, V., Vivier, E. & Ugolini, S. Biology of Tm1 cells. Immunol. Rev. 181 (in the press, 2001).

  10. Mingari, M. C. et al. Human CD8+ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations. Proc. Natl. Acad. Sci. USA 93, 12433–12438 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Coles, M. C., McMahon, C. W., Takizawa, H. & Raulet, D. H. Memory CD8 T lymphocytes express inhibitory MHC-specific Ly49 receptors. Eur. J. Immunol. 30, 236–244 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Mingari, M. C. et al. Cytolytic T lymphocytes displaying natural killer (NK)-like activity: expression of NK-related functional receptors for HLA class I molecules (p58 and CD94) and inhibitory effect on the TCR-mediated target cell lysis or lymphokine production. Int. Immunol. 7, 697–703 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Mingari, M. C. et al. HLA-class I-specific inhibitory receptors in human cytolytic T lymphocytes: molecular characterization, distribution in lymphoid tissues and co-expression by individual T cells. Int. Immunol. 9, 485–491 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Phillips, J. H., Gumperz, J. E., Parham, P. & Lanier, L. L. Superantigen-dependent, cell-mediated cytotoxicity inhibited by MHC class I receptors on T lymphocytes. Science 268, 403–405 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. D'Andrea, A., Chang, C., Phillips, J. H. & Lanier, L. L. Regulation of T cell lymphokine production by killer cell inhibitory receptor recognition of self HLA class I alleles. J. Exp. Med. 184, 789–794 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Ikeda, H. et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity 6, 199–208 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Cambiaggi, A. et al. Natural killer cell acceptance of H-2 mismatch bone marrow grafts in transgenic mice expressing HLA-Cw3 specific killer cell inhibitory receptor. Proc. Natl Acad. Sci. USA 94, 8088–8092 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cambiaggi, A. et al. Modulation of T-Cell Functions in KIR2DL3 (CD158b) Transgenic Mice. Blood 94, 2396–2402 (1999).

    CAS  PubMed  Google Scholar 

  20. Budd, R. C., Cerottini, J. C. & MacDonald, H. R. Selectively increased production of interferon-γ by subsets of Lyt-2+ and L3T4+ T cells identified by expression of Pgp-1. J. Immunol. 138, 3583–3586 (1987).

    CAS  PubMed  Google Scholar 

  21. Walunas, T. L., Bruce, D. S., Dustin, L., Loh, D. Y. & Bluestone, J. A. Ly-6C is a marker of memory CD8+ T cells. J. Immunol. 155, 1873–1883 (1995).

    CAS  PubMed  Google Scholar 

  22. Pihlgren, M., Dubois, P. M., Tomkowiak, M., Sjogren, T. & Marvel, J. Resting memory CD8+ T cells are hyperreactive to antigenic challenge in vitro. J. Exp. Med. 184, 2141–2151 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kundig, T. M. et al. On T cell memory: arguments for antigen dependence. Immunol. Rev. 150, 63–90 (1996)

    Article  CAS  PubMed  Google Scholar 

  24. Oehen, S. & Brduscha-Riem, K. Differentiation of naïve CTL to effector and memory CTL: correlation of effector function with phenotype and cell division. J. Immunol. 161, 5338–5346 (1998).

    CAS  PubMed  Google Scholar 

  25. Pircher, H.-P., Bürki, K., Lang, R., Hengartner, H. & Zinkernagel, R. M. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342, 559–561 (1989).

    Article  CAS  PubMed  Google Scholar 

  26. Diehl, L. et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nature Med. 5, 774–779 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. (* see note below) Ortaldo, J., Winkler-Pickett, R., Mason, A. T. & Mason, L. H. The Ly-49 family: regulation of cytotoxicity and cytokine production in murine CD3+ cells. J. Immunol. 160, 1158–1165 (1998).

    CAS  PubMed  Google Scholar 

  28. Marti, F. et al. LCK-phosphorylated human killer cell-inhibitory receptors recruit and activate phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA. 95, 11810–11815 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bieganowska, K. et al. Direct analysis of viral-specific CD8+ T cells with soluble HLA-A2/Tax11-19 tetramer complexes in patients with human T cell lymphotropic virus-associated myelopathy. J. Immunol. 162, 1765–1771 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank F. Vély, V. Pascal (CIML) and M. Tomkowiak (U503) for helpful comments and S. Guerder, P. Golstein, B. Malissen, P. Naquet (CIML), D. Raulet (Berkeley), N. Glaichenhaus (IPMC, Valbonne, France) and M. Bonneville (INSERM U463, Nantes, France) for stimulating discussions. We also thank P. Hoest (Laboratoire Commun de Microbiologie NSB3, Faculté de Médecine de la Timone, Marseille, France). Supported by institutional grants from INSERM, CNRS, Ministère de l'Enseignement Supérieur et de la Recherche and specific grants from Ligue Nationale contre le Cancer (to E. V., Equipe Labélisée Ligue), from Association pour la Recherche contre le Cancer (to E. V. and J. M.), from SIDACTION (to S. U.) and from the Training and Mobility of Researcher Programme (to A. C.).

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Author notes

  1. Sophie Ugolini

    Present address: Institut de Pharmacologie Moléculaire et Cellulaire, 660 Route des Lucioles, 06560, Valbonne, France

Authors and Affiliations

  1. Centre d'Immunologie INSERM/CNRS de Marseille-Luminy, Case 906, Marseille, 13288, 09, CEDEX, France

    Sophie Ugolini, Nicolas Anfossi & Eric Vivier

  2. INSERM U503, CERVI Lyon, France

    Christophe Arpin, Thierry Walzer & Jacqueline Marvel

  3. Sir William Dunn School of Pathology, University of Oxford, UK

    Anna Cambiaggi

  4. Max-Delbrueck-Center for Molecular Medicine, Berlin-Buch, Germany

    Reinhold Förster & Martin Lipp

  5. Department of Immunohematology and Bloodbank, Leiden University Medical Center, The Netherlands

    René E. M. Toes & Cornelius J. Melief

  6. Institut Universitaire de France,

    Eric Vivier

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Correspondence to Eric Vivier.

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Ugolini, S., Arpin, C., Anfossi, N. et al. Involvement of inhibitory NKRs in the survival of a subset of memory-phenotype CD8+ T cells. Nat Immunol 2, 430–435 (2001). https://doi.org/10.1038/87740

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