The Role of Stress-Induced Activation of HSP70 in Dendritic Cells, CD4+ T Cell, Memory and Adjuvanticity

Chapter
Part of the Heat Shock Proteins book series (HESP, volume 7)

Abstract

Inducible HSP70 is the hallmark of cell stress and it may mediate CD4+ T cell memory and adjuvanticity. In vitro interaction between human DC exposed to thermal or oxidative stress and CD4+ T cells elicits homeostatic memory. The mechanism involves activation of the NF-κB signalling pathway that leads to expression of membrane-associated IL-15 molecules. These interact with the IL-15 receptor complex on CD4+ T cells, activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T-cell proliferation and IFN-γ production. CD40 ligand on CD4+ T cells in turn re-activates CD40 molecules on DC. The proliferating CD4+ T cells were characterized as CD45RACD62L+ central memory cells. Importantly, the circuit is independent of antigen and MHC class-II interaction with TCR. This was confirmed and extended in vivo studies in BALB/c mice by SC immunization with ovalbumin (OVA) mixed with alum. Furthermore, inflammasomes were elicited, with significant activation of caspase 1, production of IL-1β, and adjuvanticity, demonstrated by enhancing OVA-specific serum IgG antibodies and CD4+ T cell proliferation. The novel finding that alum, the most commonly used adjuvant in vaccines induces HSP70 suggests that stress is involved in the mechanism of adjuvanticity. This was confirmed by inhibition studies with the HSP70 inhibitor PES (phenylethynesulfonamide), which inhibited both inflammasomes and the adjuvant function. Parallel studies were then pursued with oxidative, K+ releasing and a metal ionophore agents. All three stress agents induced HSP70, inflammasomes, interactions between splenic CD11c DC and CD4+ T cells and the adjuvant function. The results suggest that the three stress agents elicit HSP70, inflammasomes, homeostatic memory and adjuvanticity, commensurate with those of alum. These findings extend our understanding of the mechanism of adjuvanticity and may provide an alternative strategy in developing novel adjuvants.

References

  1. Becker T, Hartl FU, Wieland F (2002) CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 158:1277–1285CrossRefPubMedGoogle Scholar
  2. Brodsky JL, Chiosis G (2006) Hsp70 molecular chaperones: emerging roles in human disease and identification of small molecule modulators. Curr Top Med Chem 6:1215–1225CrossRefPubMedGoogle Scholar
  3. Floto RA, MacAry PA, Boname JM, Mien TS, Kampmann B, Hair JR, Huey OS, Houben EN, Pieters J, Day C, Oehlmann W, Singh M, Smith KG, Lehner PJ (2006) Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5. Science 314:454–458CrossRefPubMedGoogle Scholar
  4. Freund J, Stern ER, Pisani TM (1947) Isoallergic encephalomyelitis and radiculitis in guinea pigs after one injection of brain and mycobacteria in water-in-oil emulsion. J Exp Med 57:179Google Scholar
  5. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5:2592–2601CrossRefPubMedGoogle Scholar
  6. Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260CrossRefPubMedGoogle Scholar
  7. Goldrath AW, Bevan MJ (1999) Selecting and maintaining a diverse T-cell repertoire. Nature 402:255–262CrossRefPubMedGoogle Scholar
  8. Hammarlund E, Lewis MW, Hansen SG, Strelow LI, Nelson JA, Sexton GJ, Hanifin JM, Slifka MK (2003) Duration of antiviral immunity after smallpox vaccination. Nat Med 9:1131–1137CrossRefPubMedGoogle Scholar
  9. Hatzfeld-Charbonnier AS, Lasek A, Castera L, Gosset P, Velu T, Formstecher P, Mortier L, Marchetti P (2007) Influence of heat stress on human monocyte-derived dendritic cell functions with immunotherapeutic potential for antitumor vaccines. J Leukoc Biol 81:1179–1187CrossRefPubMedGoogle Scholar
  10. Henderson B, Pockley AG (2010) Molecular chaperones and protein-folding catalysts as intercellular signaling regulators in immunity and inflammation. J Leukoc Biol 88:445–462CrossRefPubMedGoogle Scholar
  11. Hickey TB, Thorson LM, Speert DP, Daffe M, Stokes RW (2009) Mycobacterium tuberculosis Cpn60.2 and DnaK are located on the bacterial surface, where Cpn60.2 facilitates efficient bacterial association with macrophages. Infect Immun 77:3389–3401CrossRefPubMedGoogle Scholar
  12. Intlekofer AM, Wherry EJ, Reiner SL (2006) Not-so-great expectations: re-assessing the essence of T-cell memory. Immunol Rev 211:203–213CrossRefPubMedGoogle Scholar
  13. Koishi M, Yokota S, Mae T, Nishimura Y, Kanamori S, Horii N, Shibuya K, Sasai K, Hiraoka M (2001) The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo. Clin Cancer Res 7:215–219PubMedGoogle Scholar
  14. Kool M, Petrilli V, de Smedt T, Rolaz A, Hammad H, van Nimwegen M, Bergen IM, Castillo R, Lambrecht BN, Tschopp J (2008) Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol 181:3755–3759PubMedGoogle Scholar
  15. Lehner T, Bergmeier LA, Wang Y, Tao L, Sing M, Spallek R, van der Zee R (2000) Heat shock proteins generate beta-chemokines which function as innate adjuvants enhancing adaptive immunity. Eur J Immunol 30:594–603CrossRefPubMedGoogle Scholar
  16. Leu JI, Pimkina J, Frank A, Murphy ME, George DL (2009) A small molecule inhibitor of inducible heat shock protein 70. Mol Cell 36:15–27CrossRefPubMedGoogle Scholar
  17. Li H, Willingham SB, Ting JP, Re F (2008) Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J Immunol 181:17–21PubMedGoogle Scholar
  18. Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7:31–40CrossRefPubMedGoogle Scholar
  19. Martinon F, Mayor A, Tschopp J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27:229–265CrossRefPubMedGoogle Scholar
  20. Matzinger P (2002) The danger model: a renewed sense of self. Science 296:301–305CrossRefPubMedGoogle Scholar
  21. Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62:670–684CrossRefPubMedGoogle Scholar
  22. Murali-Krishna K, Lau LL, Sambhara S, Lemonnier F, Altman J, Ahmed R (1999) Persistence of memory CD8 T cells in MHC class I-deficient mice. Science 286:1377–1381CrossRefPubMedGoogle Scholar
  23. Powers MV, Workman P (2007) Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581:3758–3769CrossRefPubMedGoogle Scholar
  24. Schmitt E, Maingret L, Puig PE, Rerole AL, Ghiringhelli F, Hammann A, Solary E, Kroemer G, Garrido C (2006) Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma. Cancer Res 66:4191–4197CrossRefPubMedGoogle Scholar
  25. Swain SL, Hu H, Huston G (1999) Class II-independent generation of CD4 memory T cells from effectors. Science 286:1381–1383CrossRefPubMedGoogle Scholar
  26. Tough DF, Sprent J (1994) Turnover of naive- and memory-phenotype T cells. J Exp Med 179:1127–1135CrossRefPubMedGoogle Scholar
  27. Varga SM, Welsh RM (1998) Detection of a high frequency of virus-specific CD4+ T cells during acute infection with lymphocytic choriomeningitis virus. J Immunol 161:3215–3218PubMedGoogle Scholar
  28. Wang WC, Goldman LM, Schleider DM, Appenheimer MM, Subjeck JR, Repasky EA, Evans SS (1998) Fever-range hyperthermia enhances L-selectin-dependent adhesion of lymphocytes to vascular endothelium. J Immunol 160:961–969PubMedGoogle Scholar
  29. Wang Y, Kelly CG, Karttunen JT, Whittall T, Lehner PJ, Duncan L, Macary P, Younson JS, Singh M, Oehlmann W, Cheng G, Bergmeier L, Lehner T (2001) CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 15:971–983CrossRefPubMedGoogle Scholar
  30. Wang Y, Kelly CG, Singh M, McGowan EG, Carraras AS, Bergmeier L, Lehner T (2002) Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding fragment of heat shock protein 70. J Immunol 169:2422–2429PubMedGoogle Scholar
  31. Wang Y, Whittall T, McGowan E, Younson J, Kelly C, Bergmeier LA, Singh M, Lehner T (2005) Identification of stimulating and inhibitory epitopes within the heat shock protein 70 molecule that modulate cytokine production and maturation of dendritic cells. J Immunol 174:3306–3316PubMedGoogle Scholar
  32. Wang Y, Seidl T, Whittall T, Babaahmady K, Lehner T (2010) Stress activated dendritic cells interact with CD4+ T cells to elicit homeostatic memory. Eur J Immunol 40:1628–1638CrossRefPubMedGoogle Scholar
  33. Wang Y, Rahman D, Lehner T (2012) A comparative study of stress-mediated immunological functions with the adjuvanticity of alum. J Biol Chem 287:17152–17160CrossRefPubMedGoogle Scholar
  34. Whittall T, Wang Y, Younson J, Kelly C, Bergmeier L, Peters B, Singh M, Lehner T (2006) Interaction between the CCR5 chemokine receptors and microbial HSP70. Eur J Immunol 36:2304–2314CrossRefPubMedGoogle Scholar
  35. Wieten L, van der Zee R, Spiering R, Wagenaar-Hilbers J, van Kooten P, Broere F, van Eden W (2010) A novel heat-shock protein coinducer boosts stress protein Hsp70 to activate T cell regulation of inflammation in autoimmune arthritis. Arthritis Rheum 62:1026–1035CrossRefPubMedGoogle Scholar
  36. Zaborina O, Li X, Cheng G, Kapatral V, Chakrabarty AM (1999) Secretion of ATP-utilizing enzymes, nucleoside diphosphate kinase and ATPase, by Mycobacterium bovis BCG: sequestration of ATP from macrophage P2Z receptors? Mol Microbiol 31:1333–1343CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Mucosal Immunology Unit, Guy’s HospitalKing’s College LondonLondonUK

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