• Ear vasculature
  • omentd2
  • Gut-Ova
  • BioRad
  • Flourescent microscope image
  • Flourescent microscope image
  • Flourescent microscope image
  • Ear vasculature

Recent Publications

High-Fat Diet Rapidly Modifies Trafficking, Phenotype, and Function of Plasmacytoid Dendritic Cells in Adipose Tissue

Stutte S, Ishikawa-Ankerhold H, Lynch L, Eickhoff S, Nasiscionyte S, Guo C, van den Heuvel D, Setzensack D, Colonna M, Maier-Begandt D, et al. High-Fat Diet Rapidly Modifies Trafficking, Phenotype, and Function of Plasmacytoid Dendritic Cells in Adipose Tissue. Immunology. 2022. Publisher's VersionAbstract

Plasmacytoid dendritic cells (pDCs) display an increased abundance in visceral adipose tissue (VAT) of humans with obesity. In the current study, we set out to decipher the molecular mechanisms of their recruitment to VAT and the functional relevance of this process. We observed increased pDC numbers in murine blood, liver, spleen, and VAT after feeding a high-fat diet (HFD) for 3 wk when compared with a standard diet. pDCs were enriched in fat-associated lymphoid clusters representing highly specific lymphoid regions within VAT. HFD led to an enlargement of fat-associated lymphoid clusters with an increased density and migratory speed of pDCs as shown by intravital multiphoton microscopy. For their recruitment into VAT, pDCs employed P-selectin with E-selectin and L-selectin being only critical in response to HFD, indicating that the molecular cues underlying pDC trafficking were dependent on the nutritional state. Subsequent recruitment steps required α4β1 and α4β7 integrins and engagement of CCR7. Application of fingolimod (FTY720) abrogated egress of pDCs from VAT, indicating the involvement of sphingosine-1-phosphate in this process. Furthermore, HFD altered pDC functions by promoting their activation and type 1 IFN expression. Blocking pDC infiltration into VAT prevented weight gain and improved glucose tolerance during HFD. In summary, a HFD fundamentally alters pDC biology by promoting their trafficking, retention, and activation in VAT, which in turn seems to regulate metabolism.

Copyright © 2022 by The American Association of Immunologists, Inc.

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Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche

Baldominos P, Barbera-Mourelle A, Barreiro O, Huang Y, Wight A, Cho J, Zhao X, Estivill G, Adam I, Sanchez X, et al. Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche. Cell. 2022;185 (10) :1694-1708. Publisher's VersionAbstract
Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.
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Quo vadis, neutrophil?

Gonzalez RJ, von Andrian UH. Quo vadis, neutrophil?. Cell. 2022;185 (5) :759-761. Publisher's VersionAbstract
Neutrophil recruitment from blood into tissues is a hallmark of inflammation and anti-microbial host defense. In this issue, De Giovanni et al. describe an unanticipated role for a serotonin metabolite, 5-HIAA, which is produced by activated platelets and mast cells and engages the orphan receptor, GPR35, to recruit neutrophils to inflamed tissues.
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ACKR1 favors transcellular over paracellular T-cell diapedesis across the blood-brain barrier in neuroinflammation in vitro

Marchetti L, Francisco D, Soldati S, Jahromi N, Barcos S, Gruber I, Pareja J, Thiriot A, von Andrian U, Deutsch U, et al. ACKR1 favors transcellular over paracellular T-cell diapedesis across the blood-brain barrier in neuroinflammation in vitro. European Journal of Immunology. 2021.Abstract
The migration of CD4+ effector/memory T cells across the blood-brain barrier (BBB) is a critical step in MS or its animal model, EAE. T-cell diapedesis across the BBB can occur paracellular, via the complex BBB tight junctions or transcellular via a pore through the brain endothelial cell body. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as in vitro model of the BBB, we here directly compared the transcriptome profile of pMBMECs favoring transcellular or paracellular T-cell diapedesis by RNA sequencing (RNA-seq). We identified the atypical chemokine receptor 1 (Ackr1) as one of the main candidate genes upregulated in pMBMECs favoring transcellular T-cell diapedesis. We confirmed upregulation of ACKR1 protein in pMBMECs promoting transcellular T-cell diapedesis and in venular endothelial cells in the CNS during EAE. Lack of endothelial ACKR1 reduced transcellular T-cell diapedesis across pMBMECs under physiological flow in vitro. Combining our previous observation that endothelial ACKR1 contributes to EAE pathogenesis by shuttling chemokines across the BBB, the present data support that ACKR1 mediated chemokine shuttling enhances transcellular T-cell diapedesis across the BBB during autoimmune neuroinflammation.
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FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity.

Mysore V, Cullere X, Mears J, Rosetti F, Okubo K, Liew PX, Zhang F, Madera-Salcedo I, Rosenbauer F, Stone RM, et al. FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity. Nature Communications. 2021.Abstract
Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8+ T cell-dependent anti-tumor immunity in mice. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, blood nAPC frequency in lupus patients correlates with disease. Moreover, anti-FcγRIIIB-antigen conjugate treatment induces nAPCs that can activate autologous T cells when using neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those vaccinated against bacterial toxins. Thus, anti-FcγRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a possible immunotherapy for cancer and infectious diseases.
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What We Do

The von Andrian lab conducts basic research in immunology using a broad range of molecular cellular and whole animal approaches. We focus on the molecular mechanisms of immune cell migration and homing in lymphoid and non-lymphoid tissues using intravital microscopy techniques.