scholarly journals Inducible Heat Shock Protein 70 Reduces T Cell Responses and Stimulatory Capacity of Monocyte-derived Dendritic Cells

2012 ◽  
Vol 287 (15) ◽  
pp. 12387-12394 ◽  
Author(s):  
Pawel Stocki ◽  
Xiao N. Wang ◽  
Anne M. Dickinson
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
T Cell Responses ◽  
Inflammatory Reactions ◽  
Cell Responses ◽  
Immature Dendritic Cells

Heat shock protein 70 (Hsp70) has gained a lot of attention in the past decade due to its potential immunoregulatory functions. Some of the described proinflammatory functions of Hsp70 became controversial as they were based on recombinant Hsp70 proteins specimens, which were later shown to be endotoxin-contaminated. In this study we used low endotoxin inducible Hsp70 (also known as Hsp72, HSPA1A), and we observed that after a 24-h incubation of monocyte-derived immature dendritic cells (mo-iDCs) with 20 μg/ml of low endotoxin Hsp70, their ability to stimulate allogenic T cells was reduced. Interestingly, low endotoxin Hsp70 also significantly reduced T cell responses when they were simulated with either IL-2 or phytohemagglutinin, therefore showing that Hsp70 could alter T cell responses independently from its effect on mo-iDCs. We also reported a greater response of Hsp70 treatment when activated versus nonactivated T cells were used. This effect of Hsp70 was similar for all tested populations of T cells that included CD3+, CD4+, or CD8+. Taken together, our observations strongly suggest that Hsp70 might dampen, rather than provoke, T cell-mediated inflammatory reactions in many clinical conditions where up-regulation of Hsp70 is observed.

scholarly journals Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease

2017 ◽  
Vol 85 (8) ◽  
Author(s):  
Lucia Trotta ◽  
Kathleen Weigt ◽  
Katina Schinnerling ◽  
Anika Geelhaar-Karsch ◽  
Gerrit Oelkers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
T Cell Responses ◽  
Tropheryma Whipplei ◽  
Content Type ◽  
Cell Responses ◽  
Ifn Γ

ABSTRACT Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward Tropheryma whipplei in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from T. whipplei was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-γ) were determined in T cells by flow cytometry. Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of T. whipplei, the proportions of activated effector CD4+ T cells, determined as CD40L+ IFN-γ+, were significantly lower in patients with CWD than in healthy controls; CD8+ T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and T. whipplei-specific degranulation, although CD69+ IFN-γ+ CD8+ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei-derived proteins. Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against T. whipplei to control bacterial spreading. The lack of specific T-cell responses against these T. whipplei-derived proteins may contribute to the pathogenesis of CWD.

scholarly journals CD4+ T cell responses to epitopes of self-heat shock protein 70 in patients with juvenile dermatomyositis

2011 ◽  
Vol 70 (Suppl 2) ◽  
pp. A44-A45 ◽  
Author(s):  
E. Koffeman ◽  
E. Elst ◽  
F. van Wijk ◽  
B. Prakken ◽  
A. van Royen-Kerkhof
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
Juvenile Dermatomyositis ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses

538 Harnessing cross-dressing dendritic cells to strengthen anti-tumor immunity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A574-A574
Author(s):  
Ellen Duong ◽  
Timothy Fessenden ◽  
Arjun Bhutkar ◽  
Stefani Spranger
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cancer Cell ◽  
Tumor Immunity ◽  
T Cell Responses ◽  
T Cell Immunity ◽  
Cell Responses ◽  
Cell Immunity ◽  
Cross Dressing

BackgroundCytotoxic (CD8+) T-cells are required for tumor eradication and durable anti-tumor immunity.1 The induction of tumor-reactive CD8+ T-cells is predominately attributed to a subset of dendritic cells (DC) called Batf3-driven DC1, given their robust ability to cross-present antigens for T-cell priming and their role in effector T-cell recruitment.2–4 Presence of the DC1 signature in tumors correlates with improved survival and response to immunotherapies.5–7 Yet, most tumors with a DC1 infiltrate still progress, suggesting that while DC1 can initiate tumor-reactive CD8+ T-cell responses, they are unable to sustain them. Therefore, there is a critical need to identify and engage additional stimulatory DC subsets to strengthen anti-tumor immunity and boost immunotherapy responses.MethodsTo identify DC subsets that drive poly-functional CD8+ T-cell responses, we compared the DC infiltrate of a spontaneously regressing tumor with a progressing tumor. Multicolor flow immunophenotyping and single-cell RNA-sequencing were used to profile the DC compartment of both tumors. IFNγ-ELISpot was performed on splenocytes to assess for systemic tumor-reactive T-cell responses. Sorted DC subsets from tumors were co-cultured with TCR-transgenic T-cells ex vivo to evaluate their stimulatory capacity. Cross-dressing (in vivo/ex vivo) was assayed by staining for transfer of tumor-derived H-2b MHC complexes to Balb/c DC, which express the H-2d haplotype. Protective systemic immunity was assayed via contralateral flank tumor outgrowth experiments.ResultsRegressor tumors were infiltrated with more cross-presenting DC1 than progressor tumors. However, tumor-reactive CD8+ T-cell responses and tumor control were preserved in Batf3-/- mice lacking DC1, indicating that anti-tumor immune responses could be induced independent of DC1. Through functional assays, we established that anti-tumor immunity against regressor tumors required CD11c+ DC and cGAS/STING-independent type-I-interferon-sensing. Single-cell RNA-sequencing of the immune infiltrate of regressor tumors revealed a novel CD11b+ DC subset expressing an interferon-stimulated gene signature (ISG+ DC). Flow studies demonstrated that ISG+ DC were more enriched in regressor tumors than progressor tumors. We showed that ISG+ DC could activate CD8+ T-cells by cross-dressing with tumor-derived peptide-MHC complexes, thereby bypassing the requirement for cross-presentation to initiate CD8+ T-cell-driven immunity. ISG+ DC highly expressed cytosolic dsRNA sensors (RIG-I/MDA5) and could be therapeutically harnessed by exogenous addition of a dsRNA analog to drive protective CD8+ T-cell responses in DC1-deficient mice.ConclusionsThe DC infiltrate in tumors can dictate the strength of anti-tumor immunity. Harnessing multiple stimulatory DC subsets, such as cross-presenting DC1 and cross-dressing ISG+ DC, provides a therapeutic opportunity to enhance anti-tumor immunity and increase immunotherapy responses.ReferencesFridman WH, et al. The immune contexture in human tumours: impact on clinical outcome. Nature Reviews Cancer 2012;12(4): p. 298–306.Hildner K, et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 2008;322(5904):p. 1097–100.Spranger S, et al. Tumor-Residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 2017;31(5):p. 711–723.e4.Roberts, EW, et al., Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 2016;30(2): p. 324–336.Broz ML, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 2014;26(5): p. 638–52.Salmon H., et al., Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity, 2016. 44(4): p. 924–38.Sánchez-Paulete AR, et al., Cancer immunotherapy with immunomodulatory anti-CD137 and Anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov, 2016;6(1):p. 71–9.

scholarly journals Batf3-Dependent Dendritic Cells Promote Optimal CD8 T Cell Responses against Respiratory Poxvirus Infection

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Pritesh Desai ◽  
Vikas Tahiliani ◽  
Georges Abboud ◽  
Jessica Stanfield ◽  
Shahram Salek-Ardakani
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Respiratory Infection ◽  
Host Resistance ◽  
T Cell Responses ◽  
Cell Responses ◽  
Ifn Γ ◽  
The Impact

ABSTRACTRespiratory infection with vaccinia virus (VacV) elicits robust CD8+T cell responses that play an important role in host resistance. In the lung, VacV encounters multiple tissue-resident antigen-presenting cell (APC) populations, but which cell plays a dominant role in priming of virus-specific CD8+effector T cell responses remains poorly defined. We used Batf3−/−mice to investigate the impact of CD103+and CD8α+dendritic cell (DC) deficiency on anti-VacV CD8+T cell responses. We found that Batf3−/−mice were more susceptible to VacV infection, exhibiting profound weight loss, which correlated with impaired accumulation of gamma interferon (IFN-γ)-producing CD8+T cells in the lungs. This was largely due to defective priming since early in the response, antigen-specific CD8+T cells in the draining lymph nodes of Batf3−/−mice expressed significantly reduced levels of Ki67, CD25, and T-bet. These results underscore a specific role for Batf3-dependent DCs in regulating priming and expansion of effector CD8+T cells necessary for host resistance against acute respiratory VacV infection.IMPORTANCEDuring respiratory infection with vaccinia virus (VacV), a member ofPoxviridaefamily, CD8+T cells play important role in resolving the primary infection. Effector CD8+T cells clear the virus by accumulating in the infected lungs in large numbers and secreting molecules such as IFN-γ that kill virally infected cells. However, precise cell types that regulate the generation of effector CD8+T cells in the lungs are not well defined. Dendritic cells (DCs) are a heterogeneous population of immune cells that are recognized as key initiators and regulators of T-cell-mediated immunity. In this study, we reveal that a specific subset of DCs that are dependent on the transcription factor Batf3 for their development regulate the magnitude of CD8+T cell effector responses in the lungs, thereby providing protection during pulmonary VacV infection.

Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2764-2771 ◽  
Author(s):  
Beth D. Harrison ◽  
Julie A. Adams ◽  
Mark Briggs ◽  
Michelle L. Brereton ◽  
John A. Liu Yin
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
T Cell Responses ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Acute Myeloid ◽  
Stimulation Of

Abstract Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor α, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

Heat-shock protein-specific T-cell responses in various stages of bovine paratuberculosis

1999 ◽  
Vol 70 (1-2) ◽  
pp. 105-115 ◽  
Author(s):  
A.P Koets ◽  
V.P.M.G Rutten ◽  
A Hoek ◽  
D Bakker ◽  
F van Zijderveld ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
T Cell Responses ◽  
Cell Responses

Potential Tolerizing Capacity of Human Dendritic Cells Featuring High Levels of Expression and Activity of the Tryptophan Metabolizing Enzyme Indoleamine 2,3 Dioxygenase.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 623-623
Author(s):  
Andreas Heitger ◽  
Birgit Juergens ◽  
Ursula Hainz ◽  
Dietmar Fuchs
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Cell Fraction ◽  
Cell Responses ◽  
Indoleamine 2,3 Dioxygenase ◽  
Ifn Γ ◽  
Human Dendritic Cells ◽  
Expression And Activity

Abstract An enhanced tryptophan metabolism mediated by the enzymatic activity of indoleamine 2,3 dioxygenase (IDO) has recently been demonstrated to profoundly affect T cell responses. By the present study we explored whether human dendritic cells (DCs) displaying high IDO expression and activity, down-regulate allogeneic T cell responses. A comparison of lipopolysaccaride (LPS), interferon-γ (IFN-γ), and CD40L as DC maturation agents showed that most abundant IDO expression and activity in DCs was observed when immature DCs were exposed to a combination of LPS and IFN-γ for 48 hours. This time period of maturation was associated with the development of a mature DC phenotype. In contrast, semi-mature DCs, i.e. DCs matured for 4 hours only, were IDO negative. In co-cultures with allogeneic T cells both types of DCs began to metabolize tryptophan, as determined by decreasing concentrations of tryptophan and increasing concentrations of kynurenines in cell culture supernatants, but mature IDO positive DCs did so at a faster rate (complete consumption of tryptophan within 16 hours of co-culture) than semi-mature DCs. A comparison of the allo-stimulatory capacity of semi-mature IDO negative DCs and mature IDO positive DCs showed that at a high DC/T cell ratio (1:1) IDO positive DCs had a significantly reduced capacity to stimulate allogeneic T cells (median 63% reduction, n=5). The reduction of the allogeneic T cell response induced by IDO positive DCs was reversed upon the addition of the IDO inhibitor methylhydantoin-tryptophan to the co-cultures, suggesting an IDO dependent mechanism. Furthermore, allogeneic T cells exposed to IDO positive DCs had an increased rate of apoptosis in the activated cell fraction and after 8 days of co-culture contained a cell fraction (~30%) displaying a CD4+CD25+highFOXP3+ phenotype. These latter cells, when enriched by fluorescent activated cell sorting (FACS), were able to suppress the proliferative response of naive T cells to anti-CD3 mediated stimulation, which indicates the generation of a regulatory T cell population by IDO positive DCs. Together, these findings suggest that the amount of IDO expression and activity by DCs is one feature to govern the type of response of stimulated T cells. Human DCs can be induced to display high levels of IDO expression and activity and, thereby, acquire the ability to effectivley modulate allogeneic T cell responses towards tolerance by eliminating allo-reactive T cells through apoptosis and augmentation of their regulatory rather than their effector potential. Our current approaches address whether this property can be employed to use DCs for the generation of allo-antigen specific tolerance in the setting of hematopoietic cell transplantation.

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