Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity

AbstractConventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear. Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells. These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.

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A Critical Role of CD40 and CD70 Signaling in Conventional Type 1 Dendritic Cells in Expansion and Antitumor Efficacy of Adoptively Transferred Tumor-Specific T Cells

The Journal of Immunology ◽

10.4049/jimmunol.2000347 ◽

2020 ◽

Vol 205 (7) ◽

pp. 1867-1877 ◽

Cited By ~ 2

Author(s):

Takaaki Oba ◽

Toshifumi Hoki ◽

Takayoshi Yamauchi ◽

Tibor Keler ◽

Henry C. Marsh ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Critical Role ◽

Antitumor Efficacy ◽

Conventional Type

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Distinct Cytokine Profiles of Neonatal Natural Killer T Cells after Expansion with Subsets of Dendritic Cells

Journal of Experimental Medicine ◽

10.1084/jem.193.10.1221 ◽

2001 ◽

Vol 193 (10) ◽

pp. 1221-1226 ◽

Cited By ~ 118

Author(s):

Norimitsu Kadowaki ◽

Svetlana Antonenko ◽

Stephen Ho ◽

Marie-Clotilde Rissoan ◽

Vassili Soumelis ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Natural Killer ◽

Critical Role ◽

Nkt Cells ◽

Dependent Manner ◽

Helper Cell Type ◽

Ifn Γ ◽

Natural Killer T

Natural killer T (NKT) cells are a highly conserved subset of T cells that have been shown to play a critical role in suppressing T helper cell type 1–mediated autoimmune diseases and graft versus host disease in an interleukin (IL)-4–dependent manner. Thus, it is important to understand how the development of IL-4– versus interferon (IFN)-γ–producing NKT cells is regulated. Here, we show that NKT cells from adult blood and those from cord blood undergo massive expansion in cell numbers (500–70,000-fold) during a 4-wk culture with IL-2, IL-7, phytohemagglutinin, anti-CD3, and anti-CD28 mAbs. Unlike adult NKT cells that preferentially produce both IL-4 and IFN-γ, neonatal NKT cells preferentially produce IL-4 after polyclonal activation. Addition of type 2 dendritic cells (DC2) enhances the development of neonatal NKT cells into IL-4+IFN-γ− NKT2 cells, whereas addition of type 1 dendritic cells (DC1) induces polarization towards IL-4−IFN-γ+ NKT1 cells. Adult NKT cells display limited plasticity for polarization induced by DC1 or DC2. Thus, newly generated NKT cells may possess the potent ability to develop into IL-4+IFN-γ− NKT2 cells in response to appropriate stimuli and may thereafter acquire the tendency to produce both IL-4 and IFN-γ.

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The Role of Human T-Lymphotropic Virus Type 1 (HTLV-1)-Infected Dendritic Cells in the Development of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

Journal of Virology ◽

10.1128/jvi.73.6.4575-4581.1999 ◽

1999 ◽

Vol 73 (6) ◽

pp. 4575-4581 ◽

Cited By ~ 61

Author(s):

Masahiko Makino ◽

Satoshi Shimokubo ◽

Shin-Ichi Wakamatsu ◽

Shuji Izumo ◽

Masanori Baba

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Virus Type ◽

Spastic Paraparesis ◽

Tropical Spastic Paraparesis ◽

Normal Donor ◽

Dependent Manner ◽

T Lymphotropic Virus

ABSTRACT The development of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is closely associated with the activation of T cells which are HTLV-1 specific but may cross-react with neural antigens (Ags). Immature dendritic cells (DCs), differentiated from normal donor monocytes by using recombinant granulocyte-macrophage colony-stimulating factor and recombinant interleukin-4, were pulsed with HTLV-1 in vitro. The pulsed DCs contained HTLV-1 proviral DNA and expressed HTLV-1 Gag Ag on their surface 6 days after infection. The DCs matured by lipopolysaccharides stimulated autologous CD4+ T cells and CD8+ T cells in a viral dose-dependent manner. However, the proliferation level of CD4+ T cells was five- to sixfold higher than that of CD8+ T cells. In contrast to virus-infected DCs, DCs pulsed with heat-inactivated virions activated only CD4+ T cells. To clarify the role of DCs in HAM/TSP development, monocytes from patients were cultured for 4 days in the presence of the cytokines. The expression of CD86 Ag on DCs was higher and that of CD1a Ag was more down-regulated than in DCs generated from normal monocytes. DCs from two of five patients expressed HTLV-1 Gag Ag. Furthermore, both CD4+ and CD8+ T cells from the patients were greatly stimulated by contact with autologous DCs pulsed with inactivated viral Ag as well as HTLV-1-infected DCs. These results suggest that DCs are susceptible to HTLV-1 infection and that their cognate interaction with T cells may contribute to the development of HAM/TSP.

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575 Regression by hetIL-15 monotherapy in different mouse breast cancer models correlates with intratumoral infiltration of a novel population of dendritic cells

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0575 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A609-A609

Author(s):

Sevasti Karaliota ◽

Dimitris Stellas ◽

Vasiliki Stravokefalou ◽

Bethany Nagy ◽

Cristina Bergamaschi ◽

...

Keyword(s):

Breast Cancer ◽

Dendritic Cells ◽

Nk Cells ◽

Flow Analysis ◽

Laboratory Animals ◽

Tumor Infiltration ◽

The Novel ◽

Phenotypic Profile ◽

Conventional Type

BackgroundIL-15 is a cytokine which stimulates the proliferation and cytotoxic function of CD8+ T and NK cells. We have produced and applied the native heterodimeric IL-15 (hetIL-15) on several preclinical models, which have supported the anti-tumor activity of hetIL-15. Based on these results, hetIL-15 has advanced to clinical trials. The objectives of this study were to explore how hetIL-15 shapes the tumor microenviroment and to characterize the interactions between tumor-infiltrating lymphoid and myeloid cells.MethodsWe studied the efficacy of locoregional administration of heterodimeric IL-15 (hetIL-15) in two different orthotopic triple-negative breast cancer (TNBC) mouse models, syngeneic for C57BL/6 and Balb/c, respectively. The effects of hetIL-15 on immune cells were analyzed by flow cytometry, immunohistochemistry (IHC) and gene expression profiling. The profile of the novel infiltrated dendritic cell populations was further explored by bulk and single cell RNAseq.Results hetIL-15 resulted in tumor eradication in 40% of treated mice and reduction of metastasis. Subsequent rechallenges with the same cell line failed to generate tumor regrowth, suggesting the development of immunological memory in hetIL-15 treated mice. hetIL-15 promoted tumor accumulation of proliferating and cytotoxic CD8+ T and NK cells. Additionally, peritumoral hetIL-15 administration resulted in an increased tumor infiltration of both conventional type 1 dendritic cells (cDC1s) and of a novel DC population found only in the hetIL-15 treated animals. Phenotypic profile analysis confirmed the expression of several cDC1 specific markers, including CD103 and IRF8 on this DC population.Transcriptomics and flow analysis of intratumoral dendritic cells indicate that the new hetIL-15 induced cells reside preferentially in the tumors and are distinct from cDC1 and cDC2 populations. Both cDC1s and the novel DC population were inversely correlated with the tumor size.ConclusionsLocoregional administration of hetIL-15 results in complete eradication of EO771 and significant reduction of 4T1 primary breast cancer tumors, prolonged survival and long-lasting specific anti-tumor immunity. hetIL-15 increases the tumor infiltration of activated T and NK cells and intensifies the tumor infiltration of conventional type 1 dendritic cells (cDC1) and a new population of dendritic cells. We propose that the anti-cancer activity of hetIL-15 in primary EO771 tumors is orchestrated by the interplay of NK, CD8+T cells, cDC1 and a novel subset of DCs with a distinct phenotypic profile. These findings suggest a role for hetIL-15 in the treatment of breast cancer.Ethics ApprovalThe study was approved by the National Cancer Institute-Frederick Animal Care and Use Committee, approval number 19–324 and was conducted in accordance with the ACUC guidelines and the NIH Guide for the Care and Use of Laboratory Animals.

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Conventional Type 2 Lung Dendritic Cells in Asthma Mouse Model Significantly Induce Follicular Helper T Cells Than Conventional Type 1

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7408 ◽

2020 ◽

Author(s):

S. Sakurai ◽

K. Furuhashi ◽

R. Horiguchi ◽

H. Yasui ◽

H. Hozumi ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mouse Model ◽

Helper T Cells ◽

Follicular Helper T Cells ◽

Follicular Helper ◽

Conventional Type ◽

Asthma Mouse Model

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DNGR-1 in dendritic cells limits tissue damage by dampening neutrophil recruitment

Science ◽

10.1126/science.aan8423 ◽

2018 ◽

Vol 362 (6412) ◽

pp. 351-356 ◽

Cited By ~ 38

Author(s):

Carlos del Fresno ◽

Paula Saz-Leal ◽

Michel Enamorado ◽

Stefanie K. Wculek ◽

Sarai Martínez-Cano ◽

...

Keyword(s):

Dendritic Cells ◽

Tissue Damage ◽

Inflammatory Responses ◽

Tissue Injury ◽

Necrotizing Pancreatitis ◽

Neutrophil Recruitment ◽

Dead Cell ◽

Cross Presentation ◽

Conventional Type

Host injury triggers feedback mechanisms that limit tissue damage. Conventional type 1 dendritic cells (cDC1s) express dendritic cell natural killer lectin group receptor-1 (DNGR-1), encoded by the gene Clec9a, which senses tissue damage and favors cross-presentation of dead-cell material to CD8+ T cells. Here we find that DNGR-1 additionally reduces host-damaging inflammatory responses induced by sterile and infectious tissue injury in mice. DNGR-1 deficiency leads to exacerbated caerulein-induced necrotizing pancreatitis and increased pathology during systemic Candida albicans infection without affecting fungal burden. This effect is B and T cell–independent and attributable to increased neutrophilia in DNGR-1–deficient settings. Mechanistically, DNGR-1 engagement activates SHP-1 and inhibits MIP-2 (encoded by Cxcl2) production by cDC1s during Candida infection. This consequently restrains neutrophil recruitment and promotes disease tolerance. Thus, DNGR-1–mediated sensing of injury by cDC1s serves as a rheostat for the control of tissue damage, innate immunity, and immunopathology.

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