scholarly journals Interaction of human heat shock protein 70 with tumor-associated peptides

2009 ◽  
Vol 390 (4) ◽  
Author(s):  
Maya J. Pandya ◽  
Henriette Bendz ◽  
Florian Manzenrieder ◽  
Elfriede Noessner ◽  
Horst Kessler ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
T Cell Activation ◽  
Heat Shock Protein 70 ◽  
Cell Activation ◽  
Peptide Sequence ◽  
Antigenic Peptides ◽  
Human Hsp70

Abstract Molecular chaperones of the heat shock protein 70 (Hsp70) family play a crucial role in the presentation of exogenous antigenic peptides by antigen-presenting cells (APCs). In a combined biochemical and immunological approach, we characterize the biochemical interaction of tumor-associated peptides with human Hsp70 and show that the strength of this interaction determines the efficacy of immunological cross-presentation of the antigenic sequences by APCs. A fluorescein-labeled cytosolic mammalian Hsc70 binding peptide is shown to interact with human Hsp70 molecules with high affinity (Kd=0.58 μm at 25°C). Competition experiments demonstrate weaker binding by Hsp70 of antigenic peptides derived from the tumor-associated proteins tyrosinase (Kd=32 μm) and melanoma antigen recognized by T cells (MART-1) (Kd=2.4 μm). Adding a peptide sequence (pep70) with high Hsp70 binding affinity (Kd=0.04 μm) to the tumor-associated peptides enables them to strongly interact with Hsp70. Presentation of tumor-associated peptides by B cells resulting in T cell activation in vitro is enhanced by Hsp70 when the tumor-associated peptides contain the Hsp70 binding sequence. This observation has relevance for vaccine design, as augmented transfer of tumor-associated antigens to APCs is closely linked to the vaccine's efficacy of T cell stimulation.

scholarly journals T Cell Activation by Heat Shock Protein 70 Vaccine Requires TLR Signaling and Scavenger Receptor Expressed by Endothelial Cells-1

2009 ◽  
Vol 183 (5) ◽  
pp. 3092-3098 ◽  
Author(s):  
Jianlin Gong ◽  
Bangmin Zhu ◽  
Ayesha Murshid ◽  
Hideki Adachi ◽  
Baizheng Song ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
T Cell Activation ◽  
Heat Shock Protein 70 ◽  
Cell Activation ◽  
Scavenger Receptor ◽  
Tlr Signaling

scholarly journals Efficient Activation of Human T Cells of Both CD4 and CD8 Subsets by Urease-Deficient Recombinant Mycobacterium bovis BCG That Produced a Heat Shock Protein 70-M. tuberculosis-Derived Major Membrane Protein II Fusion Protein

2013 ◽  
Vol 21 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Tetsu Mukai ◽  
Yumiko Tsukamoto ◽  
Yumi Maeda ◽  
Toshiki Tamura ◽  
Masahiko Makino
Keyword(s):  
T Cells ◽  
T Cell ◽  
Heat Shock ◽  
Membrane Protein ◽  
Heat Shock Protein ◽  
Fusion Protein ◽  
T Cell Activation ◽  
Heat Shock Protein 70 ◽  
Cell Activation ◽  
Content Type

ABSTRACTFor the purpose of obtainingMycobacterium bovisbacillus Calmette-Guérin (BCG) capable of activating human naive T cells, urease-deficient BCG expressing a fusion protein composed ofMycobacterium tuberculosis-derived major membrane protein II (MMP-II) and heat shock protein 70 (HSP70) of BCG (BCG-DHTM) was produced. BCG-DHTM secreted the HSP70-MMP-II fusion protein and effectively activated human monocyte-derived dendritic cells (DCs) by inducing phenotypic changes and enhanced cytokine production. BCG-DHTM-infected DCs activated naive T cells of both CD4 and naive CD8 subsets, in an antigen (Ag)-dependent manner. The T cell activation induced by BCG-DHTM was inhibited by the pretreatment of DCs with chloroquine. The naive CD8+T cell activation was mediated by the transporter associated with antigen presentation (TAP) and the proteosome-dependent cytosolic cross-priming pathway. Memory CD8+T cells and perforin-producing effector CD8+T cells were efficiently produced from the naive T cell population by BCG-DHTM stimulation. Single primary infection with BCG-DHTM in C57BL/6 mice efficiently produced T cells responsive toin vitrosecondary stimulation with HSP70, MMP-II, andM. tuberculosis-derived cytosolic protein and inhibited the multiplication of subsequently aerosol-challengedM. tuberculosismore efficiently than did vector control BCG. These results indicate that the introduction of MMP-II and HSP70 into urease-deficient BCG may be useful for improving BCG for control of tuberculosis.

scholarly journals Natural Killer and NK-Like T-Cell Activation in Colorectal Carcinoma Patients Treated with Autologous Tumor-Derived Heat Shock Protein 96

2005 ◽  
Vol 65 (9) ◽  
pp. 3942-3949 ◽  
Author(s):  
Lorenzo Pilla ◽  
Paola Squarcina ◽  
Jorgelina Coppa ◽  
Vincenzo Mazzaferro ◽  
Veronica Huber ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Colorectal Carcinoma ◽  
Heat Shock Protein ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Autologous Tumor

scholarly journals Functional evidence for TCR-intrinsic specificity for MHCII

2016 ◽  
Vol 113 (11) ◽  
pp. 3000-3005 ◽  
Author(s):  
Heather L. Parrish ◽  
Neha R. Deshpande ◽  
Jelena Vasic ◽  
Michael S. Kuhns
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Protein Tyrosine Kinase ◽  
Cell Activation ◽  
Specific Protein ◽  
Antigenic Peptides ◽  
Complex Molecules ◽  
Peptide Specificity ◽  
Contact Residues

How T cells become restricted to binding antigenic peptides within class I or class II major histocompatibility complex molecules (pMHCI or pMHCII, respectively) via clonotypic T-cell receptors (TCRs) remains debated. During development, if TCR–pMHC interactions exceed an affinity threshold, a signal is generated that positively selects the thymocyte to become a mature CD4+ or CD8+ T cell that can recognize foreign peptides within MHCII or MHCI, respectively. But whether TCRs possess an intrinsic, subthreshold specificity for MHC that facilitates sampling of the peptides within MHC during positive selection or T-cell activation is undefined. Here we asked if increasing the frequency of lymphocyte-specific protein tyrosine kinase (Lck)-associated CD4 molecules in T-cell hybridomas would allow for the detection of subthreshold TCR–MHC interactions. The reactivity of 10 distinct TCRs was assessed in response to selecting and nonselecting MHCII bearing cognate, null, or “shaved” peptides with alanine substitutions at known TCR contact residues: Three of the TCRs were selected on MHCII and have defined peptide specificity, two were selected on MHCI and have a known pMHC specificity, and five were generated in vitro without defined selecting or cognate pMHC. Our central finding is that IL-2 was made when each TCR interacted with selecting or nonselecting MHCII presenting shaved peptides. These responses were abrogated by anti-CD4 antibodies and mutagenesis of CD4. They were also inhibited by anti-MHC antibodies that block TCR–MHCII interactions. We interpret these data as functional evidence for TCR-intrinsic specificity for MHCII.

scholarly journals The Immunosuppressive Activity of Heat Shock Protein 70

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Pawel Stocki ◽  
Anne M. Dickinson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
Immune Reactivity ◽  
Antigenic Peptides ◽  
Endotoxin Contamination ◽  
Stimulatory Capacity ◽  
Clinical Conditions

Heat shock protein 70 (HSP70) has previously been described as a potent antitumour vaccine. The mechanism relied on the ability of tumour derived HSP70 to associate with antigenic peptides, which, when cross presented, elicited a T cell mediated antitumour response. Subsequently, HSP70 was incorrectly described as a potent adjuvant of innate immunity, and although mistakes in the experimental approaches were exposed and associated with endotoxin contamination in the recombinant HSP70 specimen, questions still remain regarding this matter. Here we review only publications that have cautiously addressed the endotoxin contamination problem in HSP70 in order to reveal the real immunological function of the protein. Accordingly, “endotoxin free” HSP70 stimulates macrophages and delivers antigenic peptides to APCs, which effectively prime T cells mediating an antitumour reaction. Conversely, HSP70 has potent anti-inflammatory functions as follows: regulating T cell responses, reducing stimulatory capacity of DCs, and inducing development of immunosuppressive regulatory T cells. These activities were further associated with the immune evasive mechanism of tumours and implicated in the modulation of immune reactivity in autoimmune diseases and transplant-related clinical conditions. Consequently, the role of HSP70 in immune regulation is newly emerging and contrary to what was previously anticipated.

scholarly journals Structure-activity mapping of the peptide- and force-dependent landscape of T-cell activation

2021 ◽  
Author(s):  
Yinnian Feng ◽  
Xiang Zhao ◽  
Adam K. White ◽  
K. Christopher Garcia ◽  
Polly M. Fordyce
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Antigenic Peptides ◽  
Mhc Molecules ◽  
Cell Responses ◽  
Biomechanical Force ◽  
Biomechanical Forces

SUMMARYAdaptive immunity relies on T lymphocytes that use αβ T-cell receptors (TCRs) to discriminate amongst peptides presented by MHC molecules (pMHCs). An enhanced ability to screen for pMHCs capable of inducing robust T-cell responses could have broad applications in diagnosing and treating immune diseases. T cell activation relies on biomechanical forces to initiate triggering of the TCR. Yet, most in vitro screening technologies for antigenic peptides test potential pMHCs for T cell binding without force and thus are often not predictive of activating peptides. Here, we present a technology that uses biomechanical force to initiate T cell triggering in high throughput. BATTLES (Biomechanically-Assisted T-cell Triggering for Large-scale Exogenous-pMHC Screening) displays candidate pMHCs on spectrally encoded ‘smart beads’ capable of applying physiological loads to T cells, facilitating exploration of the force- and sequence-dependent landscape of T-cell responses. BATTLES can be used to explore basic T-cell mechanobiology and T cell-based immunotherapies.

Hansenula polymorpha expressed heat shock protein gp96 exerts potent T cell activation activity as an adjuvant

2011 ◽  
Vol 151 (4) ◽  
pp. 343-349 ◽  
Author(s):  
Yang Li ◽  
Haolei Song ◽  
Jin Li ◽  
Yanzhong Wang ◽  
Xiaoli Yan ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
T Cell Activation ◽  
Cell Activation ◽  
Hansenula Polymorpha ◽  
Heat Shock Protein Gp96

scholarly journals Human Langerhans cells use an IL-15R-α/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1

Blood ◽  
2012 ◽  
Vol 119 (22) ◽  
pp. 5182-5190 ◽  
Author(s):  
Emanuela Romano ◽  
Jesse W. Cotari ◽  
Rosa Barreira da Silva ◽  
Brian C. Betts ◽  
David J. Chung ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Wilms Tumor ◽  
Antigenic Peptides ◽  
Human Cd34 ◽  
Cell Immunity ◽  
Cytokine Milieu ◽  
Self Differentiation

Abstract Human CD34+ progenitor-derived Langerhans-type dendritic cells (LCs) are more potent stimulators of T-cell immunity against tumor and viral antigens in vitro than are monocyte-derived DCs (moDCs). The exact mechanisms have remained elusive until now, however. LCs synthesize the highest amounts of IL-15R-α mRNA and protein, which binds IL-15 for presentation to responder lymphocytes, thereby signaling the phosphorylation of signal transducer and activator of transcription 5 (pSTAT5). LCs electroporated with Wilms tumor 1 (WT1) mRNA achieve sufficiently sustained presentation of antigenic peptides, which together with IL-15R-α/IL-15, break tolerance against WT1 by stimulating robust autologous, WT1-specific cytolytic T-lymphocytes (CTLs). These CTLs develop from healthy persons after only 7 days' stimulation without exogenous cytokines and lyse MHC-restricted tumor targets, which include primary WT1+ leukemic blasts. In contrast, moDCs require exogenous rhuIL-15 to phosphorylate STAT5 and attain stimulatory capacity comparable to LCs. LCs therefore provide a more potent costimulatory cytokine milieu for T-cell activation than do moDCs, thus accounting for their superior stimulation of MHC-restricted Ag-specific CTLs without need for exogenous cytokines. These data support the use of mRNA-electroporated LCs, or moDCs supplemented with exogenous rhuIL-15, as vaccines for cancer immunotherapy to break tolerance against self-differentiation antigens shared by tumors.

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