Incomplete Differentiation of Antigen-Specific CD8 T Cells in Tumor-Draining Lymph Nodes

Hargadon, Kristian M.; Brinkman, C. Colin; Sheasley-O’Neill, Stacey L.; Nichols, Lisa A.; Bullock, Timothy N. J.; Engelhard, Víctor H.

doi:10.4049/jimmunol.177.9.6081

Cited by 54 publications

(75 citation statements)

References 54 publications

(70 reference statements)

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“…In their study, melanoma-derived factors actually enhanced LPS-induced expression of select costimulatory molecules on DC2.4 cells, although cytokine and chemokine profiles were not assessed. Importantly, that previous study evaluated the effects of TCM derived from B16-F10, a different variant of B16 melanoma than the B16-F1 line that is associated with dysfunctional CD8 + T cell responses in vivo (Hargadon et al, 2006) and that suppresses DC maturation and activation in our current study. Additionally, we have recently demonstrated that a chemically mutated variant of B16, the poorly tumorigenic D5.1G4 melanoma, is significantly less immunosuppressive than B16-F1 with respect to the influence of tumor-derived factors on DC2.4 maturation and activation (Hargadon et al, 2012).…”

Section: Discussionmentioning

confidence: 86%

“…This tumor has also been shown to induce dysfunctional anti-tumor CD8 + T cell responses (Hargadon et al, 2006) that are similar to those often observed in melanoma patients Anichini et al, 2003;Zippelius et al, 2004) and it has been suggested that this dysfunction may arise from an influence of the tumor on the functional quality of DC. Because of the inherent difficulties in isolating tumor-associated DC from B16-F1 tumor-bearing animals, though, it has thus far not been possible to thoroughly examine the nature of these cells.…”

Section: The Influence Of B16-f1 Melanoma-derived Factors On Lps-indumentioning

confidence: 79%

“…The basis for this melanoma antigen-specific CD8 + T cell dysfunction in both patients and animals has remained unclear. While it is possible that tumors or tumor-derived factors directly suppress effector CD8 + T cell differentiation, it has been suggested that this T cell dysfunction might also arise from an influence of the tumor on cross-presenting DC (Hargadon et al, 2006;Ferguson et al, 2008). This latter possibility has been difficult to address by either in vivo or ex vivo analyses due to the limiting number of DC that can be isolated from melanoma patients or tumor-bearing animals.…”

Section: Discussionmentioning

confidence: 92%

“…However, in many cases dysfunctional CD8 + T cells are recovered from tumors and tumor-draining lymph nodes of melanoma patients Anichini et al, 2003;Zippelius et al, 2004). It has recently been reported in a preclinical B16-F1 murine melanoma model that CD8 + T cell responses induced against the highly conserved tyrosinase-derived Tyr 369 antigen (a well-characterized human tumor antigen) are also dysfunctional, exhibiting robust proliferation but minimal effector function (Hargadon et al, 2006). The basis for this melanoma antigen-specific CD8 + T cell dysfunction in both patients and animals has remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The majority of these studies report mechanisms of escape from tumor antigenspecific T cells, either by evasion of activated, effector T cells (through dowregulation of tumor antigen/MHC molecule expression (Restifo et al, 1993;Garrido et al, 1995) or induction of T cell death (Hahne et al, 1996;Dong et al, 2002) or by suppression of effector T cell function (Radoja et al, 2001;Blohm et al, 2002;Mortarini et al, 2003;Anichini et al, 2003;Whiteside et al, 2004;Koneru et al, 2005;Hargadon et al, 2006). Because of the importance of DC in regulating immune responses, it is appealing to speculate that tumors might also interfere with DC function.…”

Section: Ajimentioning

confidence: 99%

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Melanoma-Associated Suppression of the Dendritic Cell Lines DC2.4 and Jawsii

Hargadon

Ararso

Forrest

et al. 2012

American Journal of Immunology

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Dendritic cells function as potent regulators of both innate and adaptive immunity to tumors and the regulatory activities of these cells are tightly linked to their maturation and activation status. Despite the critical role played by dendritic cells in the induction of anti-tumor immune responses, the number of dendritic cells that can be isolated from experimental animals is limiting and often precludes in-depth analyses of these cells. To overcome this limitation, dendritic cell lines have been established and have facilitated the experimental study of dendritic cell biology. In this study we compare the dendritic cell lines DC2.4 and JAWSII as in vitro model systems for studying the influence of melanoma-derived factors on dendritic cell maturation and activation. Using flow cytometry and ELISA analyses, we evaluate the expression of costimulatory/MHC class II molecules and proinflammatory cytokines/chemokines by these dendritic cell lines in their resting state and following LPS stimulation in the presence or absence of B16-F1 melanoma-derived factors. Results: We demonstrate that soluble B16-F1-derived factors suppress the LPSinduced upregulation of CD40, CD80, CD86 and MHC class II on both the DC2.4 and JAWSII dendritic cell lines. Interestingly, LPS-induced secretion by DC2.4 cells of the proinflammatory cytokines/chemokines TNF-α, IP-10, MIP-1α, MIP-1β and MCP-1 is also altered by B16-F1-derived factors, whereas JAWSII cell cytokine/chemokine production is affected to a lesser extent by such factors, with only IL-1β and IP-10 production being suppressed. Conclusions/Recommendations: We conclude that melanoma-derived factors can suppress dendritic cell maturation/activation and that the DC2.4 and JAWSII dendritic cell lines are effective in vitro models for future studies that aim to (1) identify factors that influence both the susceptibility and the resistance of dendritic cells to tumor-mediated immunosuppression and (2) investigate the influence of tumor-altered dendritic cells on the quality of anti-tumor T cell responses.

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Section: Discussionmentioning

confidence: 86%

Section: The Influence Of B16-f1 Melanoma-derived Factors On Lps-indumentioning

confidence: 79%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Ajimentioning

confidence: 99%

See 3 more Smart Citations

Melanoma-Associated Suppression of the Dendritic Cell Lines DC2.4 and Jawsii

Hargadon

Ararso

Forrest

et al. 2012

American Journal of Immunology

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The CCL5/CCR5 axis promotes interleukin‐6 production in human synovial fibroblasts

Tang

Hsu

Fong

2010

Arthritis & Rheumatism

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Objective. CCL5 (RANTES) was originally identified as a product of activated T cells and plays a crucial role in the inflammatory response. This study was undertaken to investigate the intracellular signaling pathways involved in CCL5-induced interleukin-6 (IL-6) production in human synovial fibroblasts.Methods. CCL5-mediated IL-6 expression was assessed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The mechanisms of action of CCL5 in different signaling pathways were studied using Western blotting. Knockdown of CCR5 and protein kinase C␦ (PKC␦) protein was achieved by transfection of small interfering RNA (siRNA). Chromatin immunoprecipitation assays were used to study in vivo binding of c-Jun to the IL-6 promoter. Transient transfection was used to examine IL-6 and activator protein 1 (AP-1) activity.Results. Osteoarthritis synovial fibroblasts (OASFs) showed significant expression of CCL5 and CCR5, and expression was higher than that in normal synovial fibroblasts. Stimulation of OASFs with CCL5 induced concentration-and time-dependent increases in IL-6 production. CCL5-mediated IL-6 production was attenuated by CCR5 monoclonal antibody, CCR5 inhibitor ( Conclusion. The present results suggest that the interaction between CCL5 and CCR5 increases IL-6 production in human synovial fibroblasts via the PKC␦/ c-Src/c-Jun and AP-1 signaling pathways.

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A model system for the study of gene expression in the undergraduate laboratory

Hargadon

2016

Biochem Molecular Bio Educ

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The flow of genetic information from DNA to RNA to protein, otherwise known as the "central dogma" of biology, is one of the most basic and overarching concepts in the biological sciences. Nevertheless, numerous studies have reported student misconceptions at the undergraduate level of this fundamental process of gene expression. This study reports on the efficacy of a model system for teaching gene expression in the undergraduate laboratory. A student-centered investigation of Tgfb1 gene expression in two murine melanoma cell lines was used to emphasize not only the process of gene expression but also various research methods for studying this phenomenon. Traditional RT-PCR, quantitative real-time RT-PCR, and flow cytometry-based in situ hybridization assays were employed to study expression of this immunosuppressive cytokine gene in the highly tumorigenic B16-F1 melanoma cell line and the poorly tumorigenic D5.1G4 melanoma cell line, both at the population and single-cell levels. A pre- and post-laboratory assessment instrument demonstrated the utility of this model system in enhancing student learning both of content related to gene expression and of research methods and data analysis skills. The pedagogical approach described in this study is therefore an effective way to improve the teaching and learning of gene expression at the undergraduate level. © 2016 by The International Union of Biochemistry and Molecular Biology, 44(4):397-404, 2016.

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Incomplete Differentiation of Antigen-Specific CD8 T Cells in Tumor-Draining Lymph Nodes

Cited by 54 publications

References 54 publications

Melanoma-Associated Suppression of the Dendritic Cell Lines DC2.4 and Jawsii

Melanoma-Associated Suppression of the Dendritic Cell Lines DC2.4 and Jawsii

The CCL5/CCR5 axis promotes interleukin‐6 production in human synovial fibroblasts

A model system for the study of gene expression in the undergraduate laboratory

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