Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

T cell– and B cell–independent adaptive immunity mediated by natural killer cells

Abstract

It is commonly believed that only T lymphocytes and B lymphocytes expressing recombination-dependent antigen-specific receptors mediate contact hypersensitivity responses to haptens. Here we found that mice devoid of T cells and B cells demonstrated substantial contact hypersensitivity responses to 2,4-dinitrofluorobenzene and oxazolone. Those responses were adaptive in nature, as they persisted for at least 4 weeks and were elicited only by haptens to which mice were previously sensitized. No contact hypersensitivity was induced in mice lacking all lymphocytes, including natural killer cells. Contact hypersensitivity responses were acquired by such mice after adoptive transfer of natural killer cells from sensitized donors. Transferable hapten-specific memory resided in a Ly49C-I+ natural killer subpopulation localized specifically in donor livers. These observations indicate that natural killer cells can mediate long-lived, antigen-specific adaptive recall responses independent of B cells and T cells.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Hapten-induced DTH response in mouse bladder.
Figure 2: Hapten-induced CHS responses in ears of wild-type and Rag2−/− mice.
Figure 3: NK cell accumulation in ears of DNFB-sensitized mice versus DNFB-sensitized and challenged mice.
Figure 4: NK cells are needed to mediate CHS responses in T cell– and B cell–deficient mice.
Figure 5: Differential CHS responses of mutant mouse strains to OXA and picryl chloride.
Figure 6: A subset of hepatic NK cells carries DNFB-specific memory in sensitized Rag2−/− mice.
Figure 7: NK receptors in CHS.
Figure 8: Function of adhesion molecules and NKG2D in CHS responses in Rag2−/− mice.

References

  1. Janeway, C.A., Jr . & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  Google Scholar 

  2. Jung, D. & Alt, F.W. Unraveling V(D)J recombination; insights into gene regulation. Cell 116, 299–311 (2004).

    Article  CAS  Google Scholar 

  3. Bassing, C.H., Swat, W. & Alt, F.W. The mechanism and regulation of chromosomal V(D)J recombination. Cell 109, S45–S55 (2002).

    Article  CAS  Google Scholar 

  4. Kurtz, J. Specific memory within innate immune systems. Trends Immunol. 26, 186–192 (2005).

    Article  CAS  Google Scholar 

  5. Bloch, B. The role of idiosyncracy and allergy in dermatology. Arch. Dermat. Syph. 19, 175–197 (1929).

    Article  Google Scholar 

  6. Asherson, G.L. & Ptak, W. Contact and delayed hypersensitivity in the mouse. (I) Active sensitivity and passive transfer. Immunology 15, 405–416 (1968).

    CAS  Google Scholar 

  7. Askenase, P.W. Yes T cells, but three different T cells (αβ, γδ and NK T cells), and also B-1 cells mediate contact sensitivity. Clin. Exp. Immunol. 125, 345–350 (2001).

    Article  CAS  Google Scholar 

  8. Wang, B., Feliciani, C., Freed, I., Cai, Q. & Sauder, D.N. Insights into molecular mechanisms of contact hypersensitivity gained from gene knockout studies. J. Leukoc. Biol. 70, 185–191 (2001).

    CAS  Google Scholar 

  9. Marchal, G., Seman, M., Milon, G., Truffa-Bachi, P. & Zilberfarb, V. Local adoptive transfer of skin delayed-type hypersensitivity initiated by a single T lymphocyte. J. Immunol. 129, 954–958 (1982).

    CAS  Google Scholar 

  10. Hochgeschwender, U. et al. Dominance of one T-cells receptor in the H-2Kb/TNP response. Nature 326, 307–309 (1987).

    Article  CAS  Google Scholar 

  11. Iglesias, A., Hansen-Hagge, T., von Bonin, A. & Weltzien, H.U. Increased frequency of 2,4,6-trinitrophenyl (TNP)-specific, H-2b-restricted cytotoxic T lymphocyte precursors in transgenic mice expressing a T cell receptor chain gene from an H-2b-restricted, TNP-specific cytolytic T cell clone. Eur. J. Immunol. 22, 335–341 (1992).

    Article  CAS  Google Scholar 

  12. Bajory, Z., Hutter, J., Krombach, F. & Messmer, K. New method: the intravital videomicroscopic characteristics of the microcirculation of the urinary bladder in rats. Urol. Res. 30, 148–152 (2002).

    Article  Google Scholar 

  13. Phanuphak, P., Moorhead, J.W. & Claman, H.N. Tolerance and contact sensitivity to DNFB in mice. I. In vivo detection by ear swelling and correlation with in vitro cell stimulation. J. Immunol. 112, 115–123 (1974).

    CAS  Google Scholar 

  14. Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).

    Article  CAS  Google Scholar 

  15. Boehncke, W.H. et al. Leukocyte extravasation as a target for anti-inflammatory therapy - Which molecule to choose? Exp. Dermatol. 14, 70–80 (2005).

    Article  CAS  Google Scholar 

  16. MacDougall, J.R., Croy, B.A., Chapeau, C. & Clark, D.A. Demonstration of a splenic cytotoxic effector cell in mice of genotype SCID/SCID.BG/BG. Cell. Immunol. 130, 106–117 (1990).

    Article  CAS  Google Scholar 

  17. Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2, 223–238 (1995).

    Article  CAS  Google Scholar 

  18. Goldman, J.P. et al. Enhanced human cell engraftment in mice deficient in RAG2 and the common cytokine receptor γ chain. Br. J. Haematol. 103, 335–342 (1998).

    Article  CAS  Google Scholar 

  19. Young, W.W., Jr ., Hakomori, S.I., Durdik, J.M. & Henney, C.S. Identification of ganglio-N-tetraosylceramide as a new cell surface marker for murine natural killer (NK) cells. J. Immunol. 124, 199–201 (1980).

    CAS  Google Scholar 

  20. Schott, E., Bonasio, R. & Ploegh, H.L. Elimination in vivo of developing T cells by natural killer cells. J. Exp. Med. 198, 1213–1224 (2003).

    Article  CAS  Google Scholar 

  21. Herzog, W.R., Meade, R., Pettinicchi, A., Ptak, W. & Askenase, P.W. Nude mice produce a T cell-derived antigen-binding factor that mediates the early component of delayed-type hypersensitivity. J. Immunol. 142, 1803–1812 (1989).

    CAS  Google Scholar 

  22. Vermijlen, D. et al. High-density oligonucleotide array analysis reveals extensive differences between freshly isolated blood and hepatic natural killer cells. Eur. J. Immunol. 34, 2529–2540 (2004).

    Article  CAS  Google Scholar 

  23. Zhao, Y., Ohdan, H., Manilay, J.O. & Sykes, M. NK cell tolerance in mixed allogeneic chimeras. J. Immunol. 170, 5398–5405 (2003).

    Article  CAS  Google Scholar 

  24. Biedermann, T. et al. Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J. Exp. Med. 192, 1441–1452 (2000).

    Article  CAS  Google Scholar 

  25. Lanier, L.L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005).

    Article  CAS  Google Scholar 

  26. Kim, S. et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713 (2005).

    Article  CAS  Google Scholar 

  27. Hanke, T. et al. Direct assessment of MHC class I binding by seven Ly49 inhibitory NK cell receptors. Immunity 11, 67–77 (1999).

    Article  CAS  Google Scholar 

  28. Catalina, M.D. et al. The route of antigen entry determines the requirement for L-selectin during immune responses. J. Exp. Med. 184, 2341–2351 (1996).

    Article  CAS  Google Scholar 

  29. Staite, N.D., Justen, J.M., Sly, L.M., Beaudet, A.L. & Bullard, D.C. Inhibition of delayed-type contact hypersensitivity in mice deficient in both E-selectin and P-selectin. Blood 88, 2973–2979 (1996).

    CAS  Google Scholar 

  30. Grabbe, S. et al. β2 integrins are required for skin homing of primed T cells but not for priming naive T cells. J. Clin. Invest. 109, 183–192 (2002).

    Article  CAS  Google Scholar 

  31. Raulet, D.H. Roles of the NKG2D immunoreceptor and its ligands. Nat. Rev. Immunol. 3, 781–790 (2003).

    Article  CAS  Google Scholar 

  32. Gasser, S., Orsulic, S., Brown, E.J. & Raulet, D.H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).

    Article  CAS  Google Scholar 

  33. Bangert, C., Friedl, J., Stary, G., Stingl, G. & Kopp, T. Immunopathologic features of allergic contact dermatitis in humans: participation of plasmacytoid dendritic cells in the pathogenesis of the disease? J. Invest. Dermatol. 121, 1409–1418 (2003).

    Article  CAS  Google Scholar 

  34. Hunger, R.E., Yawalkar, N., Braathen, L.R. & Brand, C.U. The HECA-452 epitope is highly expressed on lymph cells derived from human skin. Br. J. Dermatol. 141, 565–569 (1999).

    Article  CAS  Google Scholar 

  35. von Andrian, U.H. & Mackay, C.R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000).

    Article  CAS  Google Scholar 

  36. Cumberbatch, M., Dearman, R.J., Griffiths, C.E. & Kimber, I. Epidermal Langerhans cell migration and sensitisation to chemical allergens. APMIS 111, 797–804 (2003).

    Article  CAS  Google Scholar 

  37. Rennert, P.D. et al. Essential role of lymph nodes in contact hypersensitivity revealed in lymphotoxin-α-deficient mice. J. Exp. Med. 193, 1227–1238 (2001).

    Article  CAS  Google Scholar 

  38. Martin-Fontecha, A. et al. Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nat. Immunol. 5, 1260–1265 (2004).

    Article  CAS  Google Scholar 

  39. Degli-Esposti, M.A. & Smyth, M.J. Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat. Rev. Immunol. 5, 112–124 (2005).

    Article  CAS  Google Scholar 

  40. Weninger, W. et al. Specialized contributions by α(1,3)-fucosyltransferase-IV and FucT-VII during leukocyte rolling in dermal microvessels. Immunity 12, 665–676 (2000).

    Article  CAS  Google Scholar 

  41. Morris, M.A. & Ley, K. Trafficking of natural killer cells. Curr. Mol. Med. 4, 431–438 (2004).

    Article  CAS  Google Scholar 

  42. Robert, C. & Kupper, T.S. Inflammatory skin diseases, T cells, and immune surveillance. N. Engl. J. Med. 341, 1817–1828 (1999).

    Article  CAS  Google Scholar 

  43. Geissmann, F. et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol. 3, e113 (2005).

    Article  Google Scholar 

  44. Raulet, D.H. Interplay of natural killer cells and their receptors with the adaptive immune response. Nat. Immunol. 5, 996–1002 (2004).

    Article  CAS  Google Scholar 

  45. Proteau, M.F., Rousselle, E. & Makrigiannis, A.P. Mapping of the BALB/c Ly49 cluster defines a minimal natural killer cell receptor gene repertoire. Genomics 84, 669–677 (2004).

    Article  CAS  Google Scholar 

  46. Jamieson, A.M. et al. The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 17, 19–29 (2002).

    Article  CAS  Google Scholar 

  47. Pancer, Z. et al. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430, 174–180 (2004).

    Article  CAS  Google Scholar 

  48. Galli, S.J. & Hammel, I. Unequivocal delayed hypersensitivity in mast cell-deficient and beige mice. Science 226, 710–713 (1984).

    Article  CAS  Google Scholar 

  49. Raff, M.C. Role of thymus-derived lymphocytes in the secondary humoral immune response in mice. Nature 226, 1257–1258 (1970).

    Article  CAS  Google Scholar 

  50. Snippe, H., Willems, P.J., Graven, W.G. & Kamp, E. Delayed hypersensitivity in the mouse induced by hapten-carrier complexes. Immunology 28, 897–907 (1975).

    CAS  Google Scholar 

  51. Bour, H. et al. Major histocompatibility complex class I-restricted CD8+ T cells and class II-restricted CD4+ T cells, respectively, mediate and regulate contact sensitivity to dinitrofluorobenzene. Eur. J. Immunol. 25, 3006–3010 (1995).

    Article  CAS  Google Scholar 

  52. Andrews, D.M., Scalzo, A.A., Yokoyama, W.M., Smyth, M.J. & Degli-Esposti, M.A. Functional interactions between dendritic cells and NK cells during viral infection. Nat. Immunol. 4, 175–181 (2003).

    Article  CAS  Google Scholar 

  53. Fernandez, N.C. et al. Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat. Med. 5, 405–411 (1999).

    Article  CAS  Google Scholar 

  54. Szczepanik, M. et al. γδ T cells from tolerized αβ T cell receptor (TCR)-deficient mice inhibit contact sensitivity-effector T cells in vivo, and their interferon-γ production in vitro. J. Exp. Med. 184, 2129–2139 (1996).

    Article  CAS  Google Scholar 

  55. Mora, J.R. et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003).

    Article  CAS  Google Scholar 

  56. Shaw, S.G., Maung, A.A., Steptoe, R.J., Thomson, A.W. & Vujanovic, N.L. Expansion of functional NK cells in multiple tissue compartments of mice treated with Flt3-ligand: implications for anti-cancer and anti-viral therapy. J. Immunol. 161, 2817–2824 (1998).

    CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Cheng and B. Reinhardt for technical assistance; P. Schaerli for assistance in the design of ear sheet culture experiments; J. Lieberman, K. Rajewsky, F. Alt, D. Mathis and D. Podolsky for critical reading of the manuscript; and F. Alt for providing some of the Rag2−/− mice used. Supported by the American Association for the Study of Liver Diseases (J.G.O.) and the National Institutes of Health (AI061663, HL56949 and AR42689 to U.H.v.A.; T32 DK007191 to J.G.O.; T32 HL066987 to M.G.; and T32 AR07098-31 to D.L.D.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ulrich H von Andrian.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

O'Leary, J., Goodarzi, M., Drayton, D. et al. T cell– and B cell–independent adaptive immunity mediated by natural killer cells. Nat Immunol 7, 507–516 (2006). https://doi.org/10.1038/ni1332

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1332

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing