Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

J. Cell Biol. 158 (7): 1277-1285

Copyright © 2002 by the Rockefeller University Press.

Article

CD40, an extracellular receptor for binding and uptake of Hsp70–peptide complexes

Thalia Becker1, F.-Ulrich Hartl2, and Felix Wieland1

1 Biochemie Zentrum Heidelberg (BZH), D-69120 Heidelberg, Germany
2 Department of Biochemistry, Max-Planck Institut für Biochemie, D-82152 Martinsreid, Germany

Address correspondence to Felix Wieland, Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany. Tel.: 49-6221-544150. Fax: 49-6221-544366. E-mail: felix.wieland{at}urz.uni-heidelberg.de

Abstract: Tumor and viral antigens elicit a potent immune response by heat shock protein–dependent uptake of antigenic peptide with subsequent presentation by MHC I. Receptors on antigen-presenting cells that specifically bind and internalize a heat shock protein–peptide complex have not yet been identified. Here, we show that cells expressing CD40, a cell surface protein crucial for B cell function and autoimmunity, specifically bind and internalize human Hsp70 with bound peptide. Binding of Hsp70–peptide complex to the exoplasmic domain of CD40 is mediated by the NH2-terminal nucleotide–binding domain of Hsp70 in its ADP state. The Hsp70 cochaperone Hip, but not the bacterial Hsp70 homologue DnaK, competes formation of the Hsp70–CD40 complex. Binding of Hsp70-ADP to CD40 is strongly increased in the presence of Hsp70 peptide substrate, and induces signaling via p38. We suggest that CD40 is a cochaperone-like receptor mediating the uptake of exogenous Hsp70–peptide complexes by macrophages and dendritic cells.

Key Words: heat shock protein receptor; immune response; cross priming; co-chaperone; CD40; antigen-presenting cell

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Mutant HSP70 Reverses Autoimmune Depigmentation in Vitiligo.
J. A. Mosenson, A. Zloza, J. D. Nieland, E. Garrett-Mayer, J. M. Eby, E. J. Huelsmann, P. Kumar, C. J. Denman, A. T. Lacek, F. J. Kohlhapp, et al. (2013)
Science Translational Medicine 5, 174ra28
   Abstract »    Full Text »    PDF »
An Anti-Nucleic Acid Antibody Delivers Antigen to the Cross-Presentation Pathway in Dendritic Cells and Potentiates Therapeutic Antitumor Effects.
C. D. Pham, M.-Y. Woo, Y.-S. Kim, S. Park, and M.-H. Kwon (2012)
J. Immunol. 189, 5755-5763
   Abstract »    Full Text »    PDF »
Crucial Role of CD40 Signaling in Vascular Wall Cells in Neointimal Formation and Vascular Remodeling After Vascular Interventions.
Z. Song, R. Jin, S. Yu, A. Nanda, D. N. Granger, and G. Li (2012)
Arterioscler Thromb Vasc Biol 32, 50-64
   Abstract »    Full Text »    PDF »
Tyrosine nitration limits stretch-induced CD40 expression and disconnects CD40 signaling in human endothelial cells.
A. H. Wagner, A. Hildebrandt, S. Baumgarten, A. Jungmann, O. J. Muller, V. S. Sharov, C. Schoneich, and M. Hecker (2011)
Blood 118, 3734-3742
   Abstract »    Full Text »    PDF »
CD204 Suppresses Large Heat Shock Protein-Facilitated Priming of Tumor Antigen gp100-Specific T Cells and Chaperone Vaccine Activity against Mouse Melanoma.
J. Qian, H. Yi, C. Guo, X. Yu, D. Zuo, X. Chen, J. M. Kane III, E. A. Repasky, J. R. Subjeck, and X.-Y. Wang (2011)
J. Immunol. 187, 2905-2914
   Abstract »    Full Text »    PDF »
Bacterial Virulence in the Moonlight: Multitasking Bacterial Moonlighting Proteins Are Virulence Determinants in Infectious Disease.
B. Henderson and A. Martin (2011)
Infect. Immun. 79, 3476-3491
   Abstract »    Full Text »    PDF »
The Ras Signaling Inhibitor LOX-PP Interacts with Hsp70 and c-Raf To Reduce Erk Activation and Transformed Phenotype of Breast Cancer Cells.
S. Sato, P. C. Trackman, J. M. Maki, J. Myllyharju, K. H. Kirsch, and G. E. Sonenshein (2011)
Mol. Cell. Biol. 31, 2683-2695
   Abstract »    Full Text »    PDF »
Tumor-Produced Secreted Form of Binding of Immunoglobulin Protein Elicits Antigen-Specific Tumor Immunity.
Y. Tamura, Y. Hirohashi, G. Kutomi, K. Nakanishi, K. Kamiguchi, T. Torigoe, and N. Sato (2011)
J. Immunol. 186, 4325-4330
   Abstract »    Full Text »    PDF »
Targeting to Static Endosome Is Required for Efficient Cross-Presentation of Endoplasmic Reticulum-Resident Oxygen-Regulated Protein 150-Peptide Complexes.
G. Kutomi, Y. Tamura, K. Okuya, T. Yamamoto, Y. Hirohashi, K. Kamiguchi, J. Oura, K. Saito, T. Torigoe, S. Ogawa, et al. (2009)
J. Immunol. 183, 5861-5869
   Abstract »    Full Text »    PDF »
Mycobacterium tuberculosis Cpn60.2 and DnaK Are Located on the Bacterial Surface, Where Cpn60.2 Facilitates Efficient Bacterial Association with Macrophages.
T. B. M. Hickey, L. M. Thorson, D. P. Speert, M. Daffe, and R. W. Stokes (2009)
Infect. Immun. 77, 3389-3401
   Abstract »    Full Text »    PDF »
Mitochondrial heat shock protein (HSP) 70 synergizes with HSP60 in transducing endothelial cell apoptosis induced by anti-HSP60 autoantibody.
J.-E. Alard, M. Dueymes, R. A. Mageed, A. Saraux, P. Youinou, and C. Jamin (2009)
FASEB J 23, 2772-2779
   Abstract »    Full Text »    PDF »
CD40-Independent Engagement of Mammalian hsp70 by Antigen-Presenting Cells.
R. J. Binder (2009)
J. Immunol. 182, 6844-6850
   Abstract »    Full Text »    PDF »
Heat shock protein 70 (HSP70) induces cytotoxicity of T-helper cells.
C. Figueiredo, M. Wittmann, D. Wang, R. Dressel, A. Seltsam, R. Blasczyk, and B. Eiz-Vesper (2009)
Blood 113, 3008-3016
   Abstract »    Full Text »    PDF »
Heat Shock Protein 70, Released from Heat-Stressed Tumor Cells, Initiates Antitumor Immunity by Inducing Tumor Cell Chemokine Production and Activating Dendritic Cells via TLR4 Pathway.
T. Chen, J. Guo, C. Han, M. Yang, and X. Cao (2009)
J. Immunol. 182, 1449-1459
   Abstract »    Full Text »    PDF »
Calcium Signaling in Dendritic Cells by Human or Mycobacterial Hsp70 Is Caused by Contamination and Is Not Required for Hsp70-mediated Enhancement of Cross-presentation.
H. Bendz, B.-C. Marincek, F. Momburg, J. W. Ellwart, R. D. Issels, P. J. Nelson, and E. Noessner (2008)
J. Biol. Chem. 283, 26477-26483
   Abstract »    Full Text »    PDF »
Human recombinant heat shock protein 70 affects the maturation pathways of dendritic cells in vitro and has an in vivo adjuvant activity.
B. Valentinis, A. Capobianco, F. Esposito, A. Bianchi, P. Rovere-Querini, A. A. Manfredi, and C. Traversari (2008)
J. Leukoc. Biol. 84, 199-206
   Abstract »    Full Text »    PDF »
Hsp70 Translocates into the Plasma Membrane after Stress and Is Released into the Extracellular Environment in a Membrane-Associated Form that Activates Macrophages.
V. L. Vega, M. Rodriguez-Silva, T. Frey, M. Gehrmann, J. C. Diaz, C. Steinem, G. Multhoff, N. Arispe, and A. De Maio (2008)
J. Immunol. 180, 4299-4307
   Abstract »    Full Text »    PDF »
The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation.
R. M. Srivastava, C. Varalakshmi, and A. Khar (2008)
J. Immunol. 180, 1117-1130
   Abstract »    Full Text »    PDF »
Human Heat Shock Protein 70 Enhances Tumor Antigen Presentation through Complex Formation and Intracellular Antigen Delivery without Innate Immune Signaling.
H. Bendz, S. C. Ruhland, M. J. Pandya, O. Hainzl, S. Riegelsberger, C. Brauchle, M. P. Mayer, J. Buchner, R. D. Issels, and E. Noessner (2007)
J. Biol. Chem. 282, 31688-31702
   Abstract »    Full Text »    PDF »
Cancer Immunotherapy Using Irradiated Tumor Cells Secreting Heat Shock Protein 70.
C.-L. Chang, Y.-C. Tsai, L. He, T.-C. Wu, and C.-F. Hung (2007)
Cancer Res. 67, 10047-10057
   Abstract »    Full Text »    PDF »
Efficient Cross-Presentation by Heat Shock Protein 90-Peptide Complex-Loaded Dendritic Cells via an Endosomal Pathway.
T. Kurotaki, Y. Tamura, G. Ueda, J. Oura, G. Kutomi, Y. Hirohashi, H. Sahara, T. Torigoe, H. Hiratsuka, H. Sunakawa, et al. (2007)
J. Immunol. 179, 1803-1813
   Abstract »    Full Text »    PDF »
Chaperone-rich cell lysate embedded with BCR-ABL peptide demonstrates enhanced anti-tumor activity against a murine BCR-ABL positive leukemia.
K. L. Kislin, M. T. Marron, G. Li, M. W. Graner, and E. Katsanis (2007)
FASEB J 21, 2173-2184
   Abstract »    Full Text »    PDF »
Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy.
E. Schmitt, M. Gehrmann, M. Brunet, G. Multhoff, and C. Garrido (2007)
J. Leukoc. Biol. 81, 15-27
   Abstract »    Full Text »    PDF »
Role of Scavenger Receptors in the Binding and Internalization of Heat Shock Protein 70.
J. R. Theriault, H. Adachi, and S. K. Calderwood (2006)
J. Immunol. 177, 8604-8611
   Abstract »    Full Text »    PDF »
Extracellular Targeting of Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 170 Enhances Tumor Immunity to a Poorly Immunogenic Melanoma.
X.-Y. Wang, H. Arnouk, X. Chen, L. Kazim, E. A. Repasky, and J. R. Subjeck (2006)
J. Immunol. 177, 1543-1551
   Abstract »    Full Text »    PDF »
High-Affinity Interactions between Peptides and Heat Shock Protein 70 Augment CD8+ T Lymphocyte Immune Responses.
J. B. Flechtner, K. P. Cohane, S. Mehta, P. Slusarewicz, A. K. Leonard, B. H. Barber, D. L. Levey, and S. Andjelic (2006)
J. Immunol. 177, 1017-1027
   Abstract »    Full Text »    PDF »
Nuclear Localization in the Biology of the CD40 Receptor in Normal and Neoplastic Human B Lymphocytes.
Y.-C. Lin-Lee, L. V. Pham, A. T. Tamayo, L. Fu, H.-J. Zhou, L. C. Yoshimura, G. L. Decker, and R. J. Ford (2006)
J. Biol. Chem. 281, 18878-18887
   Abstract »    Full Text »    PDF »
Interactions of Tumor Necrosis Factor (TNF) and TNF Receptor Family Members in the Mouse and Human.
C. Bossen, K. Ingold, A. Tardivel, J.-L. Bodmer, O. Gaide, S. Hertig, C. Ambrose, J. Tschopp, and P. Schneider (2006)
J. Biol. Chem. 281, 13964-13971
   Abstract »    Full Text »    PDF »
Anti-HSP auto-antibodies enhance HSP-induced pro-inflammatory cytokine production in human monocytic cells via Toll-like receptors.
S.-i. Yokota, S. Minota, and N. Fujii (2006)
Int. Immunol. 18, 573-580
   Abstract »    Full Text »    PDF »
Hyperthermia Enhances CTL Cross-Priming.
H. Shi, T. Cao, J. E. Connolly, L. Monnet, L. Bennett, S. Chapel, C. Bagnis, P. Mannoni, J. Davoust, A. K. Palucka, et al. (2006)
J. Immunol. 176, 2134-2141
   Abstract »    Full Text »    PDF »
Heat Shock Proteins as Endogenous Adjuvants in Sterile and Septic Inflammation.
F. J. Quintana and I. R. Cohen (2005)
J. Immunol. 175, 2777-2782
   Abstract »    Full Text »    PDF »
Chaperone proteins and brain tumors: Potential targets and possibletherapeutics.
M. W. Graner and D. D. Bigner (2005)
Neuro Oncology 7, 260-278
   Abstract »    PDF »
Combination of Imatinib Mesylate with Autologous Leukocyte-Derived Heat Shock Protein and Chronic Myelogenous Leukemia.
Z. Li, Y. Qiao, B. Liu, E. J. Laska, P. Chakravarthi, J. M. Kulko, R. D. Bona, M. Fang, U. Hegde, V. Moyo, et al. (2005)
Clin. Cancer Res. 11, 4460-4468
   Abstract »    Full Text »    PDF »
Identification of Stimulating and Inhibitory Epitopes within the Heat Shock Protein 70 Molecule That Modulate Cytokine Production and Maturation of Dendritic Cells.
Y. Wang, T. Whittall, E. McGowan, J. Younson, C. Kelly, L. A. Bergmeier, M. Singh, and T. Lehner (2005)
J. Immunol. 174, 3306-3316
   Abstract »    Full Text »    PDF »
Pathogen-Induced Apoptotic Neutrophils Express Heat Shock Proteins and Elicit Activation of Human Macrophages.
L. Zheng, M. He, M. Long, R. Blomgran, and O. Stendahl (2004)
J. Immunol. 173, 6319-6326
   Abstract »    Full Text »    PDF »
Hsc70 and Hsp70 interact with phosphatidylserine on the surface of PC12 cells resulting in a decrease of viability.
N. ARISPE, M. DOH, O. SIMAKOVA, B. KURGANOV, and A. DE MAIO (2004)
FASEB J 18, 1636-1645
   Abstract »    Full Text »    PDF »
Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming.
C. A. Martin, S. E. Carsons, R. Kowalewski, D. Bernstein, M. Valentino, and F. Santiago-Schwarz (2003)
J. Immunol. 171, 5736-5742
   Abstract »    Full Text »    PDF »
Cell Surface-bound Heat Shock Protein 70 (Hsp70) Mediates Perforin-independent Apoptosis by Specific Binding and Uptake of Granzyme B.
C. Gross, W. Koelch, A. DeMaio, N. Arispe, and G. Multhoff (2003)
J. Biol. Chem. 278, 41173-41181
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882