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Title Using distinct molecular signatures of human monocytes and dendritic cells to predict adjuvant activity and pyrogenicity of TLR agonists
Author Richard Kenmoe Kamgang, Ines Ramos, Lurdes Rodrigues Duarte, Mascia Ghielmetti, Marina Freudenberg, Clemens Dahinden, Elisabetta Padovan
Abstract We present a systematic study that defines molecular profiles of adjuvanticity and pyrogenicity induced by agonists of human Toll-like receptor molecules in vitro. Using P3CSK4, Lipid A and Poly I:C as model adjuvants we show that all three molecules enhance the expansion of IFNγ /CD4 T cells from their naïve precursors following priming with allogeneic DC in vitro. In contrast, co-culture of naive CD4 T cells with allogeneic monocytes and TLR2/TLR4 agonists only resulted in enhanced T cell proliferation. Distinct APC molecular signatures in response to each TLR agonist underline the dual effect observed on T cell responses. Using protein and gene expression assays, we show that TNF-α and CXCL10 represent DC-restricted molecular signatures of TLR2/TLR4 and TLR3 activation, respectively, in sharp contrast to IL-6 produced by monocytes upon stimulation with P3CSK4 and Lipid A. Furthermore, although all TLR agonists are able to up-regulate proIL-1β specific gene in both cell types, only monocyte activation with Lipid A results in detectable IL-1β release. These molecular profiles, provide a simple screen to select new immune enhancers of human Th1 responses suitable for clinical application.
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References
1. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the
adaptive immune responses. Nat Immunol 5:987–9952. Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev
Immunol 21:335–376
3. Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J,
Schoen RT, Medzhitov R, Fikrig E, Flavell RA (2002) Hyporesponsiveness
to vaccination with Borrelia burgdorferi OspA in
humans and in TLR1- and TLR2-deWcient mice. Nat Med 8:878–
884
4. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition
of double-stranded RNA and activation of NF-kappaB by
Toll-like receptor 3. Nature 413:732–738
5. Poltorak A, Ricciardi-Castagnoli P, Citterio S, Beutler B (2000)
Physical contact between lipopolysaccharide and toll-like receptor
4 revealed by genetic complementation. Proc Natl Acad Sci USA
97:2163–2167
6. Sporri R, Reis e Sousa C (2005) InXammatory mediators are
insuYcient for full dendritic cell activation and promote expansion
of CD4 T cell populations lacking helper function. Nat Immunol
6:163–170
7. Padovan E, Landmann RM, De Libero G (2007) How pattern recognition
receptor triggering inXuences T cell responses: a new
look into the system. Trends Immunol 28:308–314
8. Kanzler H, Barrat FJ, Hessel EM, CoVman RL (2007) Therapeutic
targeting of innate immunity with Toll-like receptor agonists and
antagonists. Nat Med 13:552–559
9. Pashine A, Valiante NM, Ulmer JB (2005) Targeting the innate
immune response with improved vaccine adjuvants. Nat Med
11:S63–S68
10. Visintin A, Mazzoni A, Spitzer JH, Wyllie DH, Dower SK, Segal
DM (2001) Regulation of Toll-like receptors in human monocytes
and dendritic cells. J Immunol 166:249–255
11. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia
A (2001) Specialization and complementarity in microbial molecule
recognition by human myeloid and plasmacytoid dendritic
cells. Eur J Immunol 31:3388–3393
12. Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan
F, Liu YJ (2001) Subsets of human dendritic cell precursors
express diVerent toll-like receptors and respond to diVerent microbial
antigens. J Exp Med 194:863–869
13. Trombetta ES, Mellman I (2005) Cell biology of antigen processing
in vitro and in vivo. Annu Rev Immunol 23:975–1028
14. Freudenberg MA, Fomsgaard A, Mitov I, Galanos C (1989)
ELISA for antibodies to lipid A, lipopolysaccharides and other
hydrophobic antigens. Infection 17:322–328
15. Schramm G, Falcone FH, Gronow A, Haisch K, Mamat U, DoenhoV
MJ, Oliveira G, Galle J, Dahinden CA, Haas H (2003) Molecular
characterization of an interleukin-4-inducing factor from
Schistosoma mansoni eggs. J Biol Chem 278:18384–18392
16. Reschner A, Moretta A, Landmann R, Heberer M, Spagnoli GC,
Padovan E (2003) The ester-bonded palmitoyl side chains of
Pam3CysSerLys4 lipopeptide account for its powerful adjuvanticity
to HLA class I-restricted CD8 T lymphocytes. Eur J Immunol
33:2044–2052
17. Ghielmetti M, Reschner A, Zwicker M, Padovan E (2005) Synthetic
bacterial lipopeptide analogs: structural requirements for
adjuvanticity. Immunobiology 210:211–215
18. Kapsenberg ML (2003) Dendritic-cell control of pathogen-driven
T-cell polarization. Nat Rev Immunol 3:984–993
19. Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA (2000)
A novel polymorphism in the toll-like receptor 2 gene and its potential
association with staphylococcal infection. Infect Immun
68:6398–6401
20. Lorenz E, Mira JP, Frees KL, Schwartz DA (2002) Relevance of
mutations in the TLR4 receptor in patients with gram-negative
septic shock. Arch Intern Med 162:1028–1032
21. Schroeder JT, Bieneman AP, Xiao H, Chichester KL, Vasagar K,
Saini S, Liu MC (2005) TLR9- and FcepsilonRI-mediated responses
oppose one another in plasmacytoid dendritic cells by
down-regulating receptor expression. J Immunol 175:5724–5731
22. van Duin D, Mohanty S, Thomas V, Ginter S, Montgomery RR,
Fikrig E, Allore HG, Medzhitov R, Shaw AC (2007) Age-associated
defect in human TLR-1/2 function. J Immunol 178:970–975
23. Sallusto F, Lanzavecchia A (1994) EYcient presentation of soluble
antigen by cultured human dendritic cells is maintained by
granulocyte/macrophage colony-stimulating factor plus interleukin
4 and downregulated by tumor necrosis factor alpha. J Exp
Med 179:1109–1118
24. Thoma-Uszynski S, Kiertscher SM, Ochoa MT, Bouis DA, Norgard
MV, Miyake K, Godowski PJ, Roth MD, Modlin RL (2000)
Activation of toll-like receptor 2 on human dendritic cells triggers
induction of IL-12, but not IL-10. J Immunol 165:3804–3810
25. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H,
Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S (2003)
Role of adaptor TRIF in the MyD88-independent toll-like receptor
signaling pathway. Science 301:640–643
26. Weighardt H, Jusek G, Mages J, Lang R, Hoebe K, Beutler B,
Holzmann B (2004) IdentiWcation of a TLR4- and TRIF-dependent
activation program of dendritic cells. Eur J Immunol 34:558–
564
27. Matsumoto M, Funami K, Tanabe M, Oshiumi H, Shingai M, Seto
Y, Yamamoto A, Seya T (2003) Subcellular localization of Tolllike
receptor 3 in human dendritic cells. J Immunol 171:3154–
3162
28. Dinarello CA (2004) Infection, fever, and exogenous and endogenous
pyrogens: some concepts have changed. J Endotoxin Res
10:201–222
29. Cunha FQ, Assreuy J, Moss DW, Rees D, Leal LM, Moncada S,
Carrier M, O'Donnell CA, Liew FY (1994) DiVerential induction
of nitric oxide synthase in various organs of the mouse during endotoxaemia:
role of TNF-alpha and IL-1-beta. Immunology
81:211–215
30. Freudenberg MA, Galanos C (1990) Bacterial lipopolysaccharides:
structure, metabolism and mechanisms of action. Int Rev
Immunol 6:207–221
31. Bessler WG, Mittenbuhler K, Esche U, Huber M (2003) Lipopeptide
adjuvants in combination treatment. Int Immunopharmacol
3:1217–1224
32. Heikenwalder M, Polymenidou M, Junt T, Sigurdson C, Wagner
H, Akira S, Zinkernagel R, Aguzzi A (2004) Lymphoid follicle
destruction and immunosuppression after repeated CpG oligodeoxynucleotide
administration. Nat Med 10:187–192
33. Okemoto K, Kawasaki K, Hanada K, Miura M, Nishijima M
(2006) A potent adjuvant monophosphoryl lipid A triggers various
immune responses, but not secretion of IL-1beta or activation of
caspase-1. J Immunol 176:1203–1208
Keywords Adjuvant screening - Human - Dendritic cell - Monocytes - Th1 cells
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