Abstract B071: Enhanced IL-12 production and T cell stimulation ability by dendritic cells matured in presence of GMP-grade Toll-like receptor ligands and IFN-γ

Abstract Dendritic cells (DCs) are essential for the initiation of acquired immune responses through antigen acquisition, migration, maturation, and T-cell stimulation. One of the critical mechanisms in this response is the process actin nucleation and polymerization, which is mediated by several groups of proteins, including mammalian Diaphanous-related formins (mDia). However, the role of mDia in DCs remains unknown. Herein, we examined the role of mDia1 (one of the isoforms of mDia) in DCs. Although the proliferation and maturation of bone marrow-derived DCs were comparable between control C57BL/6 and mDia1-deficient (mDia1−/−) mice, adhesion and spreading to cellular matrix were impaired in mDia1−/− bone marrow–derived DCs. In addition, fluorescein isothiocyanate-induced cutaneous DC migration to draining lymph nodes in vivo and invasive migration and directional migration to CCL21 in vitro were suppressed in mDia1−/− DCs. Moreover, sustained T-cell interaction and T-cell stimulation in lymph nodes were impaired by mDia1 deficiency. Consistent with this, the DC-dependent delayed hypersensitivity response was attenuated by mDia1-deficient DCs. These results suggest that actin polymerization, which is mediated by mDia1, is essential for several aspects of DC-initiated acquired immune responses.

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Dendritic cells are susceptible to infection with wild-type adenovirus, inducing a differentiation arrest in precursor cells and inducing a strong T-cell stimulation

Journal of General Virology ◽

10.1099/vir.0.013920-0 ◽

2009 ◽

Vol 91 (5) ◽

pp. 1150-1154 ◽

Cited By ~ 7

Author(s):

T. Kessler ◽

K. Hamprecht ◽

T. Feuchtinger ◽

G. Jahn

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Precursor Cells ◽

Wild Type ◽

Cell Stimulation ◽

T Cell Stimulation

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Selected Toll-like Receptor Ligands and Viruses Promote Helper-Independent Cytotoxic T Cell Priming by Upregulating CD40L on Dendritic Cells

Immunity ◽

10.1016/j.immuni.2008.11.015 ◽

2009 ◽

Vol 30 (2) ◽

pp. 218-227 ◽

Cited By ~ 71

Author(s):

Susan Johnson ◽

Yifan Zhan ◽

Robyn M. Sutherland ◽

Adele M. Mount ◽

Sammy Bedoui ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cytotoxic T Cell ◽

Toll Like Receptor ◽

Receptor Ligands ◽

T Cell Priming

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Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells

Journal of Experimental Medicine ◽

10.1084/jem.20050940 ◽

2005 ◽

Vol 202 (7) ◽

pp. 885-891 ◽

Cited By ~ 383

Author(s):

Kuibeom Ko ◽

Sayuri Yamazaki ◽

Kyoko Nakamura ◽

Tomohisa Nishioka ◽

Keiji Hirota ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Immunity ◽

Cd8 T Cells ◽

Effector T Cells ◽

Tumor Rejection ◽

Cell Stimulation ◽

T Cell Stimulation ◽

Ifn Γ ◽

Advanced Tumors

T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor family–related protein (GITR) can evoke effective tumor immunity. A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. A large number of CD4+ and CD8+ T cells, including interferon (IFN)-γ–secreting cells, infiltrated regressing tumors. Tumor-specific IFN-γ–secreting CD4+ and CD8+ T cells also increased in the spleen. The treatment led to tumor rejection in IFN-γ–intact mice but not IFN-γ–deficient mice. Furthermore, coadministration of anti-GITR and anti–CTLA-4 mAbs had a synergistic effect, leading to eradication of more advanced tumors. In contrast, coadministration of anti-CD25 and anti-GITR mAbs was less effective than anti-GITR treatment alone, because anti-CD25 depleted both CD25+-activated effector T cells and CD25+CD4+ naturally occurring regulatory T (T reg) cells. Importantly, CD4+ T cells expressing the T reg–specific transcription factor Foxp3 predominantly infiltrated growing tumors in control mice, indicating that tumor-infiltrating natural Foxp3+CD25+CD4+ T reg cells may hamper the development of effective tumor immunity. Taken together, T cell stimulation through GITR attenuates T reg–mediated suppression or enhances tumor-killing by CD4+ and CD8+ effector T cells, including those secreting IFN-γ, or both. Agonistic anti-GITR mAb is therefore instrumental in treating advanced cancers.

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