Tracking Dendritic Cells In Vivo: Insights Into DC Biology and Function

Classical dendritic cells (cDCs) in mice have been divided into 2 major subsets based on the expression of nuclear transcription factors: a CD8+Irf8+Batf3 dependent (DC1) subset, and a CD8-Irf4+ (DC2) subset. We found that the CD8+DC1 subset can be further divided into CD8+DC1a and CD8+DC1b subsets by differences in surface receptors, gene expression, and function. Whereas all 3 DC subsets can act alone to induce potent Th1 cytokine responses to class I and II MHC restricted peptides derived from ovalbumin (OVA) by OT-I and OT-II transgenic T cells, only the DC1b subset could effectively present glycolipid antigens to natural killer T (NKT) cells. Vaccination with OVA protein pulsed DC1b and DC2 cells were more effective in reducing the growth of the B16-OVA melanoma as compared to pulsed DC1a cells in wild type mice. In conclusion, the Batf3-/- dependent DC1 cells can be further divided into two subsets with different immune functional profiles in vitro and in vivo.

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Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma

Blood ◽

10.1182/blood-2005-06-2486 ◽

2006 ◽

Vol 107 (6) ◽

pp. 2432-2439 ◽

Cited By ~ 68

Author(s):

Siqing Wang ◽

Jing Yang ◽

Jianfei Qian ◽

Michele Wezeman ◽

Larry W. Kwak ◽

...

Keyword(s):

Dendritic Cells ◽

P38 Mapk ◽

Neutralizing Antibodies ◽

Molecular Mechanisms ◽

Mapk Signaling ◽

Janus Kinase ◽

Mitogen Activated Protein Kinase ◽

Patients With Cancer ◽

And Function

AbstractDendritic cells (DCs) from patients with cancer are functionally defective, but the molecular mechanisms underlying these defects are poorly understood. In this study, we used the murine 5TGM1 myeloma model to examine the effects and mechanisms of tumor-derived factors on the differentiation and function of DCs. Myeloma cells or tumor culture conditioning medium (TCCM) were shown to inhibit the differentiation and function of BM-derived DCs (BMDCs), as evidenced by the down-regulated expression of DC-related surface molecules, decreased IL-12, and compromised capacity of the cells to activate allospecific T cells. Moreover, TCCM-treated BMDCs were inferior to normal BMDCs at priming tumor-specific immune responses in vivo. Neutralizing antibodies against IL-6, IL-10, and TGF-β partially abrogated the effects. TCCM treatment activated p38 mitogen-activated protein kinase (MAPK) and Janus kinase (JNK) but inhibited extracellular regulated kinase (ERK). Inhibiting p38 MAPK restored the phenotype, cytokine secretion, and function of TCCM-treated BMDCs. BMDCs from cultures with TCCM and p38 inhibitor was as efficacious as normal BMDCs at inducing tumor-specific antibody, type 1 T cell, and cytotoxic T lymphocyte (CTL) responses and at prolonging mouse survival. Thus, our results suggested that tumor-induced p38 MAPK activation and ERK inhibition in DCs may be a new mechanism for tumor evasion and that regulating these pathways during DC differentiation provides new strategies for generating potent DC vaccines for immunotherapy in patients with cancer. (Blood. 2006;107:2432-2439)

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Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria

Journal of Experimental Medicine ◽

10.1084/jem.20121972 ◽

2013 ◽

Vol 210 (8) ◽

pp. 1635-1646 ◽

Cited By ~ 64

Author(s):

Alberto Pinzon-Charry ◽

Tonia Woodberry ◽

Vivian Kienzle ◽

Virginia McPhun ◽

Gabriela Minigo ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Acute Infection ◽

Plasmodium Infection ◽

Spontaneous Apoptosis ◽

Cross Sectional ◽

And Function ◽

Immature Cells

Malaria causes significant morbidity worldwide and a vaccine is urgently required. Plasmodium infection causes considerable immune dysregulation, and elicitation of vaccine immunity remains challenging. Given the central role of dendritic cells (DCs) in initiating immunity, understanding their biology during malaria will improve vaccination outcomes. Circulating DCs are particularly important, as they shape immune responses in vivo and reflect the functional status of other subpopulations. We performed cross-sectional and longitudinal assessments of the frequency, phenotype, and function of circulating DC in 67 Papuan adults during acute uncomplicated P. falciparum, P. vivax, and convalescent P. falciparum infections. We demonstrate that malaria patients display a significant reduction in circulating DC numbers and the concurrent accumulation of immature cells. Such alteration is associated with marked levels of spontaneous apoptosis and impairment in the ability of DC to mature, capture, and present antigens to T cells. Interestingly, sustained levels of plasma IL-10 were observed in patients with acute infection and were implicated in the induction of DC apoptosis. DC apoptosis was reversed upon IL-10 blockade, and DC function recovered when IL-10 levels returned to baseline by convalescence. Our data provide key information on the mechanisms behind DC suppression during malaria and will assist in developing strategies to better harness DC’s immunotherapeutic potential.

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The Requirement of Membrane Lymphotoxin for the Presence of Dendritic Cells in Lymphoid Tissues

Journal of Experimental Medicine ◽

10.1084/jem.190.5.629 ◽

1999 ◽

Vol 190 (5) ◽

pp. 629-638 ◽

Cited By ~ 113

Author(s):

Qiang Wu ◽

Yang Wang ◽

Jing Wang ◽

Elizabeth O. Hedgeman ◽

Jeffrey L. Browning ◽

...

Keyword(s):

Dendritic Cells ◽

Lymphoid Tissues ◽

Tnf Receptor ◽

Wild Type ◽

Normal Numbers ◽

And Function ◽

Necrosis Factor ◽

Cell Zone

Although several cytokines, including tumor necrosis factor (TNF), can promote the growth of dendritic cells (DCs) in vitro, the cytokines that naturally regulate DC development and function in vivo have not been well defined. Here, we report that membrane lymphotoxin (LT), instead of TNF, regulates the migration of DCs in the spleen. LTα−/− mice, lacking membrane LTα/β and LTα3, show markedly reduced numbers of DCs in the spleen. Unlike wild-type mice and TNF−/− mice that have densely clustered DCs in the T cell zone and around the marginal zone, splenic DCs in LTα−/− mice are randomly distributed. The reduced number of DCs in lymphoid tissues of LTα−/− mice is associated with an increased number of DCs in nonlymphoid tissues. The number of splenic DCs in LTα−/− mice is restored when additional LT-expressing cells are provided. Blocking membrane LTα/β in wild-type mice markedly diminishes the accumulation of DCs in lymphoid tissues. These data suggest that membrane LT is an essential ligand for the presence of DCs in the spleen. Mice deficient in TNF receptor, which is the receptor for both soluble LTα3 and TNF-α3 trimers, have normal numbers of DCs. However, LTβR−/− mice show reduced numbers of DCs, similar to the mice lacking membrane LT α/β. Taken together, these results support the notion that the signaling via LTβR by membrane LTα/β is required for the presence of DCs in lymphoid tissues.

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Expression of the Phosphatase Ppef2 Controls Survival and Function of CD8+ Dendritic Cells

10.1101/374652 ◽

2018 ◽

Author(s):

Markus Zwick ◽

Thomas Ulas ◽

Yi-Li Cho ◽

Christine Ried ◽

Leonie Grosse ◽

...

Keyword(s):

Dendritic Cells ◽

Protein Phosphatase ◽

Apoptotic Cell ◽

Model Systems ◽

Toll Like Receptor ◽

Cell Responses ◽

Ef Hands ◽

And Function ◽

Dc Maturation

AbstractApoptotic cell death of Dendritic cells (DCs) is critical for immune homeostasis. Although intrinsic mechanisms controlling DC death have not been fully characterized up to now, experimentally enforced inhibition of DC-death causes various autoimmune diseases in model systems. We have generated mice deficient for Protein Phosphatase with EF-Hands 2 (Ppef2), which is selectively expressed in CD8+ DCs, but not in other related DC subtypes such as tissue CD103+ DCs. Ppef2 is down-regulated rapidly upon maturation of DCs by toll-like receptor stimuli, but not upon triggering of CD40. Ppef2-deficient CD8+ DCs accumulate the pro-apoptotic Bcl-2-like protein 11 (Bim) and show increased apoptosis and reduced competitve repopulation capacities. Furthermore, Ppef2−/−CD8+ DCs have strongly diminished antigen presentation capacities in vivo, as CD8+ T cells primed by Ppef2−/− CD8+ DCs undergo reduced expansion. In conclusion, our data suggests that Ppef2 is crucial to support survival of immature CD8+ DCs, while Ppef2 down-regulation during DC-maturation limits T cell responses.

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Tumor Evasion of the Immune System: Inhibiting p38 MAP Kinase Signaling Restores the Function of Dendritic Cells.

Blood ◽

10.1182/blood.v106.11.2512.2512 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2512-2512

Author(s):

Qing Yi ◽

Siqing Wang ◽

Jing Yang ◽

Jianfei Wang ◽

Michele Wezeman ◽

...

Keyword(s):

Dendritic Cells ◽

P38 Mapk ◽

Neutralizing Antibodies ◽

Molecular Mechanisms ◽

P38 Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Myeloma Cells ◽

And Function

Abstract Dendritic cells (DCs) from cancer patients are functionally defective, however, molecular mechanisms underlying are still poorly understood. In this study, we used the murine 5TGM1 myeloma model to examine the effect and mechanism of tumor-derived factors on the differentiation and function of DCs. Myeloma cells (5TGM1) or tumor culture conditioning medium (TCCM) were shown to inhibit differentiation and function of BM-derived DCs (BMDCs), evidenced by the downregulated expression of DC-related surface molecules, decreased IL-12 but increased IL-10 secretion, and compromised capacity of the cells to activate allospecific T cells in vitro. Similar results were obtained with other murine myeloma cells MOPC-315 and MPC-11. Moreover, TCCM-treated BMDCs were inferior to normal BMDCs at priming tumor-specific humoral and cellular immune responses in vivo (in the 5TGM1 mouse model). Neutralizing antibodies against IL-6, IL-10, and TGF-β partially abrogated the effects. TCCM treatment activated p38 mitogen-activated protein kinase (MAPK) and JNK but inhibited extracellular signal-related kinase (ERK). Inhibiting p38 MAPK by three different specific inhibitors was found to restore the phenotype, cytokine secretion, and function of TCCM-treated BMDCs. Vaccinating mice with BMDCs obtained from cultures in which both TCCM and p38 inhibitor were added was as efficacious as normal BMDCs at inducing tumor-specific antibody, type-1 (IFN-γ) T-cell, and CTL responses. Thus, our results suggest that tumor-induced p38 MAPK activation and ERK inhibition in DCs may be a new mechanism for tumor evasion, and regulating these signaling pathways in vivo or during DC differentiation may provide new strategies for generating potent DC vaccines for immunotherapy of multiple myeloma and other tumors.

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