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Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination

Nature Medicine volume 11, pages 748–756 (2005)Cite this article

Abstract

Efficient boosting of memory T-cell numbers to protective levels generally requires a relatively long interval between immunizations. Decreasing this interval could be crucial in biodefense and cancer immunotherapy, in which rapid protective responses are essential. Here, we show that vaccination with peptide-coated dendritic cells (DCs) generated CD8+ T cells with the phenotype and function of memory cells within 4–6 d. These early memory CD8+ T cells underwent vigorous secondary expansion in response to a variety of booster immunizations, leading to elevated numbers of effector and memory T cells and enhanced protective immunity. Coinjection of CpG oligodeoxynucleotides, potent inducers of inflammation that did not alter the duration of DC antigen display, prevented the rapid generation of memory T cells in wild-type mice but not in mice lacking the interferon (IFN)-γ receptor. These data show that DC vaccination stimulates a pathway of accelerated generation of memory T cells, and suggest that events of inflammation, including the action of IFN-γ on the responding T cells, control the rate of development of memory CD8+ T cells.

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Figure 1: Accelerated response to booster infection after DC-immunization.
Figure 2: Increased numbers of memory phenotype CD8+ T cells in DC+LM mice enhance protective immunity.
Figure 3: Amplified secondary memory in DC-immunized mice in response to multiple boosting regimens and against weak antigens.
Figure 4: Rapid generation of memory CD8+ T cells and vigorous secondary expansion after booster infection of DC-immunized L. monocytogenes–immune hosts.
Figure 5: DC immunization accelerates the transition of CD8+ T cells from an effector to memory phenotype.
Figure 6: Inflammation prevents accelerated generation of memory CD8+ T cells and early prime-boost.

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References

  1. Kaech, S.M., Wherry, E.J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol. 2, 251–262 (2002).

    Article  CAS  Google Scholar 

  2. Badovinac, V.P., Porter, B.B. & Harty, J.T. Programmed contraction of CD8(+) T-cells after infection. Nat. Immunol. 3, 619–626 (2002).

    Article  CAS  Google Scholar 

  3. Badovinac, V.P., Messingham, K.A., Hamilton, S.E. & Harty, J.T. Regulation of CD8+ T-cells undergoing primary and secondary responses to infection in the same host. J. Immunol. 170, 4933–4942 (2003).

    Article  CAS  Google Scholar 

  4. Woodland, D.L. Jump-starting the immune system: prime–boosting comes of age. Trends Immunol. 25, 98–104 (2004).

    Article  CAS  Google Scholar 

  5. Mercado, R. et al. Early programming of T-cell populations responding to bacterial infection. J. Immunol. 165, 6833–6839 (2000).

    Article  CAS  Google Scholar 

  6. Kaech, S.M. & Ahmed, R. Memory CD8+ T-cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat. Immunol. 2, 415–422 (2001).

    Article  CAS  Google Scholar 

  7. van Stipdonk, M.J., Lemmens, E.E. & Schoenberger, S.P. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat. Immunol. 2, 423–429 (2001).

    Article  CAS  Google Scholar 

  8. Wong, P. & Pamer, E.G. Cutting edge: antigen-independent CD8 T-cell proliferation. J. Immunol. 166, 5864–5868 (2001).

    Article  CAS  Google Scholar 

  9. Kaech, S.M., Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8 T-cell differentiation. Cell 111, 837–851 (2002).

    Article  CAS  Google Scholar 

  10. Sallusto, F., Geginat, J. & Lanzavecchia, A. Central Memory and Effector Memory T-cell Subsets: Function, Generation, and Maintenance. Annu. Rev. Immunol. 22, 683–709 (2004).

    Article  Google Scholar 

  11. Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T-cell subsets. Nat. Immunol. 4, 225–234 (2003).

    Article  CAS  Google Scholar 

  12. Roberts, A.D. & Woodland, D.L. Cutting Edge: Effector Memory CD8+ T-cells Play a Prominent Role in Recall Responses to Secondary Viral Infection in the Lung. J. Immunol. 172, 6533–6537 (2004).

    Article  CAS  Google Scholar 

  13. Badovinac, V.P. & Harty, J.T. Memory lanes. Nat. Immunol. 4, 212–213 (2003).

    Article  CAS  Google Scholar 

  14. Hamilton, S.E. & Harty, J.T. Quantitation of CD8+ T-cell expansion, memory, and protective immunity after immunization with peptide coated dendritic cells. J. Immunol. 169, 4936–4944 (2002).

    Article  Google Scholar 

  15. Hamilton, S.E., Porter, B.B., Messingham, K.A.N., Badovinac, V.P. & Harty, J.T. MHC class Ia-restricted memory T-cells inhibit expansion of a nonprotective MHC class Ib (H2–M3)-restricted memory response. Nat. Immunol. 5, 159–168 (2004).

    Article  CAS  Google Scholar 

  16. Pamer, E.G. Immune responses to Listeria monocytogenes . Nat. Rev. Immunol. 4, 812–823 (2004).

    Article  CAS  Google Scholar 

  17. Wong, P., Lara-Tejero, M., Ploss, A., Leiner, I. & Pamer, E.G. Rapid development of T-cell memory. J. Immunol. 172, 7239–7245 (2004).

    Article  CAS  Google Scholar 

  18. Kaech, S.M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T-cells that give rise to long-lived memory cells. Nat. Immunol. 4, 1191–1198 (2003).

    Article  CAS  Google Scholar 

  19. Schluns, K.S., Kieper, W.C., Jameson, S.C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T-cells in vivo. Nat. Immunol. 1, 426–432 (2000).

    Article  CAS  Google Scholar 

  20. Schluns, K.S. & Lefrancois, L. Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3, 269–279 (2003).

    Article  CAS  Google Scholar 

  21. Harrington, L.E., Galvan, M., Baum, L.G., Altman, J.D. & Ahmed, R. Differentiating between memory and effector CD8 T-cells by altered expression of cell surface O-glycans. J. Exp. Med. 191, 1241–1246 (2000).

    Article  CAS  Google Scholar 

  22. An, L.L., Pamer, E. & Whitton, J.L. A recombinant minigene vaccine containing a nonameric cytotoxic-T-lymphocyte epitope confers limited protection against Listeria monocytogenes infection. Infect. Immun. 64, 1685–1693 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Brundage, R.A., Smith, G.A., Camilli, A., Theriot, J.A. & Portnoy, D.A. Expression and phosphorylation of the Listeria monocytogenes ActA protein in mammalian cells. Proc. Natl Acad. Sci. USA 90, 11890–11894 (1993).

    Article  CAS  Google Scholar 

  24. Mackaness, G.B. Cellular resistance to infection. J. Exp. Med. 1, 381–406 (1962).

    Article  Google Scholar 

  25. Edelson, B.T., Cossart, P. & Unanue, E.R. Cutting edge: paradigm revisited: antibody provides resistance to Listeria infection. J. Immunol. 163, 4087–4090 (1999).

    CAS  Google Scholar 

  26. Kerksiek, K.M., Busch, D.H., Pilip, I.M., Allen, S.E. & Pamer, E.G. H2–M3restricted T-cells in bacterial infection: rapid primary but diminished memory responses. J. Exp. Med. 190, 195–204 (1999).

    Article  CAS  Google Scholar 

  27. Sprent, J. & Surh, C.D. T-cell memory. Annu. Rev. Immunol. 20, 551–579 (2002).

    Article  CAS  Google Scholar 

  28. Seder, R.A. & Ahmed, R. Similarities and differences in CD4+ and CD8+ effector and memory T-cell generation. Nat. Immunol. 4, 835–842 (2003).

    Article  CAS  Google Scholar 

  29. Hendriks, J., Gravestein, L.A., Tesselaar, K., van Lier, R.A., Schumacher, T.N. & Borst, J. CD27 is required for generation and long-term maintenance of T-cell immunity. Nat. Immunol. 1, 433–440.

  30. Huster, K.M. et al. Selective expression of IL-7 receptor on memory T-cells identifies early CD40L-dependent generation of distinct CD8+ memory T-cell subsets. Proc. Natl Acad. Sci. USA 101, 5610–5615 (2004).

    Article  CAS  Google Scholar 

  31. Badovinac, V.P., Porter, B.B. & Harty, J.T. CD8+ T-cell contraction is controlled by early inflammation. Nat. Immunol. 5, 809–817 (2004).

    Article  CAS  Google Scholar 

  32. Shen, H. et al. Compartmentalization of bacterial antigens: differential effects on priming of CD8 T-cells and protective immunity. Cell 92, 535–545 (1998).

    Article  CAS  Google Scholar 

  33. Hogquist, K.A. et al. T-cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  Google Scholar 

  34. Foulds, K.E. et al. Cutting edge: CD4 and CD8 T-cells are intrinsically different in their proliferative responses. J. Immunol. 168, 1528–1532 (2002).

    Article  CAS  Google Scholar 

  35. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

    Article  CAS  Google Scholar 

  36. Heath, W.R. & Carbone, F.R. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19, 47–64 (2001).

    Article  CAS  Google Scholar 

  37. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    Article  CAS  Google Scholar 

  38. Bouwer, H.G., Moors, M. & Hinrichs, D.J. Elimination of the listeriolysin O directed immune response by conservative alteration of the immunodominant listeriolysin O amino acid 91 to 99 epitope. Infect. Immun. 64, 3728–3735 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Krieg, A.M. CpG motifs: the active ingredient in bacterial extracts? Nat. Med. 9, 831–835 (2003).

    Article  CAS  Google Scholar 

  40. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  Google Scholar 

  41. Wagner, H. Interactions between bacterial CpG-DNA and TLR9 bridge innate and adaptive immunity. Curr. Opin. Microbiol. 5, 62–69 (2002).

    Article  CAS  Google Scholar 

  42. Haring, J.S., Corbin, G.A. & Harty, J.T. Dynamic regulation of IFN-γ signaling in antigen-specific CD8+ T-cells responding to infection. J. Immunol. 174, 6791–6802 (2005).

    Article  CAS  Google Scholar 

  43. Badovinac, V.P., Tvinnereim, A.R. & Harty, J.T. Regulation of antigen specific CD8(+) T-cell homeostasis by perforin and interferon-gamma. Science 290, 1354–1357 (2000).

    Article  CAS  Google Scholar 

  44. Paczesny, S. et al. Expansion of Melanoma-specific Cytolytic CD8+ T-cell Precursors in Patients with Metastatic Melanoma Vaccinated with CD34+ Progenitor-derived Dendritic Cells. J. Exp. Med. 199, 1503–1511 (2004).

    Article  CAS  Google Scholar 

  45. Figdor, C.G., de Vries, I.J., Lesterhuis, W.J. & Melief, C.J.M. Dendritic cell immunotherapy: mapping the way. Nat. Med. 10, 475–480 (2004).

    Article  CAS  Google Scholar 

  46. Pernis, A. et al. Lack of interferon γ receptor beta chain and the prevention of interferon γ signaling in TH1 cells. Science 269, 245–247 (1995).

    Article  CAS  Google Scholar 

  47. Harty, J.T. & Bevan, M.J. Specific immunity to Listeria monocytogenes in the absence of IFN gamma. Immunity 3, 109–117 (1995).

    Article  CAS  Google Scholar 

  48. Busch, D.H., Pilip, I.M., Vijh, S. & Pamer, E.G. Coordinate regulation of complex T-cell populations responding to bacterial infection. Immunity 8, 353–362 (1998).

    Article  CAS  Google Scholar 

  49. Badovinac, V.P. & Harty, J.T. Intracellular staining for TNF and IFNgamma detects different frequencies of antigen-specific CD8(+) T-cells. J. Immunol. Methods 238, 107–117 (2000).

    Article  CAS  Google Scholar 

  50. Badovinac, V.P., Hamilton, S.E. & Harty, J.T. Viral infection results in massive CD8+ T-cell expansion and mortality in vaccinated perforin deficient mice. Immunity 18, 463–474 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Podyminogin for technical assistance, S. Perlman and S. Varga for critical review of the manuscript, J. L. Whitton for Vaccinia virus, L. Lefrancois and H. Shen for LM-OVA, H.G. Archie Bower for DP-L2528 and the US National Institutes of Health (NIH) tetramer core (Atlanta, Georgia) for providing tetramers. Supported by NIH grants AI42767, AI46653, AI50073 (to J.T.H.), T32AI0726 (to K.A.N.M and J.S.H) and T32AI007511 (to K.A.N.M).

Author information

Author notes

  1. Vladimir P Badovinac and Kelly A N Messingham: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology, 3-512 Bowen Science Building, 51 Newton Road, University of Iowa, Iowa City, 52240, Iowa, USA

    Vladimir P Badovinac, Kelly A N Messingham, Jodie S Haring & John T Harty

  2. Interdisciplinary Graduate Program in Immunology, University of Iowa, 1190 Medical Laboratories, Iowa City, 52240, Iowa, USA

    Ali Jabbari & John T Harty

Authors
  1. Vladimir P Badovinac
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  2. Kelly A N Messingham
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  5. John T Harty
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Corresponding author

Correspondence to John T Harty.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Increased frequencies of memory CD8+ T cells in lymphoid and nonlymphoid tissues in DC+LM mice. (PDF 168 kb)

Supplementary Fig. 2

The magnitude of expansion and memory CD8+ T-cell numbers in DC-immunized mice are determined by dose of L. monocytogenes booster infection. (PDF 95 kb)

Supplementary Fig. 3

Increased MHC class Ib CD8+ T-cell response after early booster infection of DC-fMIGWII immunized mice. (PDF 67 kb)

Supplementary Fig. 4

Antigen-specific CD8+ T cells exhibit phenotypic and functional characteristics of memory cells early after DC-peptide immunization. (PDF 69 kb)

Supplementary Fig. 5

DC-peptide immunization accelerates the transition of CD8+ T cells from an effector to memory phenotype. (PDF 71 kb)

Supplementary Fig. 6

CD8+ T-cell priming in the context of infection prevents accelerated memory generation and early prime-boost response. (PDF 69 kb)

Supplementary Fig. 7

In vitro maturation of DC with CpG does not prevent rapid memory CD8+ T-cell generation in vivo. (PDF 111 kb)

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Badovinac, V., Messingham, K., Jabbari, A. et al. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat Med 11, 748–756 (2005). https://doi.org/10.1038/nm1257

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