scholarly journals Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma

2018 ◽  
Author(s):  
Carlos R. Figueiredo ◽  
Ricardo A. Azevedo ◽  
Sasha Mousdell ◽  
Pedro T. Resende-Lara ◽  
Lucy Ireland ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Metastatic Melanoma ◽  
Immune Cells ◽  
Tumour Microenvironment ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Adaptive Immune Cells ◽  
Cancer Immunotherapies

ABSTRACTMounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells’ immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

Calreticulin Promotes Immunity Against Acute Myeloid Leukemia Cells in Vivo

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 996-996
Author(s):  
Xiufen Chen ◽  
Dominick Fosco ◽  
Douglas E. Kline ◽  
Justin Kline
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Surface ◽  
Vector Control ◽  
Immune Cells ◽  
Myeloid Leukemia ◽  
Innate Immune ◽  
Innate Immune Cells

Abstract Pre-apoptotic cancer cells release internalized calreticulin (CRT) to their surface prior to death, which acts as an ‘eat-me’ signal to local phagocytes. Chemotherapy and irradiation, which can induce immunogenic cell death through CRT translocation, can also result in local and/or systemic immune suppression in the host. To bypass the requirement of exposing the host to chemotherapy to induce translocation of CRT to the cell surface, murine acute myeloid leukemia (AML) cells (C1498), were engineered to constitutively express cell surface CRT (C1498.CRT). Vector control C1498 or C1498.CRT cells were inoculated intravenously (IV) into C57BL/6 mice. Significantly prolonged survival was observed in hosts harboring C1498.CRT versus vector control C1498 cells systemically. The survival benefit were abrogated in both Rag2-/- hosts or by depletion of T cells with anti-CD4 plus anti-CD8 antibodies, arguing that the immune-mediated effect of cell-surface CRT expression is dependent upon a functional adaptive immune system. More strikingly, systemic inoculation with C1498.CRT cells expressing the model SIYRYYGL (SIY) peptide antigen (C1498.SIY.CRT cells) resulted in almost complete protection from AML development (>90% long term survival vs. 10% of C1498.SIY vector control cells). All animals surviving a primary C1498.SIY.CRT challenge rejected a subsequent re-challenge with C1498.SIY cells, suggesting that CRT-expressing AML cells promote immunologic memory. Significantly enhanced expansion and unregulated IFNγ production were observed among SIY-specific T cell receptor transgenic CD8+ 2C T cells following their adoptive transfer into hosts bearing C1498.SIY.CRT AML cells versus vector control C1498.SIY cells. Interestingly, CRT expression on AML cells did not promote their in vivo phagocytosis by innate immune cells, specifically splenic CD8a+ dendritic cells known to engulf AML cells following their IV inoculation. IL-12 production by CD8α+CD11c+ dendritic cells which had engulfed C1498 and C1498.CRT cells in vivo was similarly induced, and cross-presentation of the SIY antigen to 2C T cells ex vivo by purified CD8a+DCs following in vivo exposure to C1498.SIY or C1498.SIY.CRT cells was also similar. In conclusion, it is clear that expression on CRT on the surface of AML cells leads to robust leukemia-specific T cell activation and expansion resulting in prolonged leukemia-specific survival in AML-bearing animals. Although a direct effect of CRT on innate immune cells, such as dendritic cells, is suspected, the molecular mechanism underlying the “CRT effect” remains unclear, and is being explored further through gene expression analysis in purified DCs which have engulfed CRT-expressing or control AML cells in vivo, as well as in animals genetically deficient in the putative CRT receptor, LRP, in dendritic cells. It will be of interest to analyze spontaneous CRT expression on AML cells from human samples and to correlate cell surface CRT expression with the presence or absence of spontaneous T cell responses to known AML antigens and with clinical outcomes. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Role of Syk/CARD9-Coupled C-Type Lectin Receptors in Immunity toMycobacterium tuberculosisInfections

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Mohlopheni Jackson Marakalala ◽  
Lisa M. Graham ◽  
Gordon D. Brown
Keyword(s):  
Immune Response ◽  
Pattern Recognition ◽  
Mycobacterium Tuberculosis ◽  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Lectin Receptors ◽  
Molecular Patterns

There is increasing interest in understanding the mechanisms underlying the interactions that occur betweenMycobacterium tuberculosisand host innate immune cells. These cells express pattern recognition receptors (PRRs) which recognise mycobacterial pathogen-associated molecular patterns (PAMPs) and which can influence the host immune response to the infection. Although many of the PRRs appear to be redundant in the control ofM. tuberculosisinfectionin vivo, recent discoveries have revealed a key, nonredundant, role of the Syk/CARD9 signalling pathway in antimycobacterial immunity. Here we review these discoveries, as well as recent data investigating the role of the Syk/CARD9-coupled PRRs that have been implicated in mycobacterial recognition, including Dectin-1 and Mincle.

scholarly journals Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 456 ◽  
Author(s):  
Philippe Saas ◽  
Alexis Varin ◽  
Sylvain Perruche ◽  
Adam Ceroi
Keyword(s):  
Dendritic Cells ◽  
Lipid Metabolism ◽  
Nuclear Receptors ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Plasmacytoid Dendritic Cell ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Cells ◽  
Immune Functions

There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-β). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. Some differences may be related to the origin of PDC (human versus mouse PDC or blood-sorted versus FLT3 ligand stimulated-bone marrow-sorted PDC). The kinetics of glycolysis may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR, explaining a delayed glycolysis. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statins or LXR agonists) in these cells. Finally, lipid-activated nuclear receptors (i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-κB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role.

scholarly journals Helminth Infections: Recognition and Modulation of the Immune Response by Innate Immune Cells

2018 ◽  
Vol 9 ◽  
Author(s):  
Claudia Cristina Motran ◽  
Leonardo Silvane ◽  
Laura Silvina Chiapello ◽  
Martin Gustavo Theumer ◽  
Laura Fernanda Ambrosio ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Helminth Infections

scholarly journals Natural Killer Dendritic Cells Enhance Immune Responses Elicited byα-Galactosylceramide-Stimulated Natural Killer T Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-18 ◽  
Author(s):  
Sung Won Lee ◽  
Hyun Jung Park ◽  
Nayoung Kim ◽  
Seokmann Hong
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Natural Killer ◽  
Immune Cells ◽  
Tumor Antigens ◽  
Nkt Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Natural Killer T

Natural killer dendritic cells (NKDCs) possess potent anti-tumor activity, but the cellular effect of NKDC interactions with other innate immune cells is unclear. In this study, we demonstrate that the interaction of NKDCs and natural killer T (NKT) cells is required for the anti-tumor immune responses that are elicited byα-galactosylceramide (α-GC) in mice. The rapid and strong expression of interferon-γby NKDCs afterα-GC stimulation was dependent on NKT cells. Various NK and DC molecular markers and cytotoxic molecules were up-regulated followingα-GC administration. This up-regulation could improve NKDC presentation of tumor antigens and increase cytotoxicity against tumor cells. NKDCs were required for the stimulation of DCs, NK cells, and NKT cells. The strong anti-tumor immune responses elicited byα-GC may be due to the down-regulation of regulatory T cells. Furthermore, the depletion of NKDCs dampened the tumor clearance mediated byα-GC-stimulated NKT cellsin vivo. Taken together, these results indicate that complex interactions of innate immune cells might be required to achieve optimal anti-tumor immune responses during the early stages of tumorigenesis.

The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance

2013 ◽  
Vol 109 (03) ◽  
pp. 399-406 ◽  
Author(s):  
Triantafyllos Chavakis ◽  
Jindrich Chmelar ◽  
Kyoung-Jin Chung
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Immune Cells ◽  
Cytotoxic T Cells ◽  
Innate Immune ◽  
Low Grade ◽  
Innate Immune Cells ◽  
Metabolic Complications ◽  
Adaptive Immune Cells

SummaryObesity is characterised by a chronic state of low-grade inflammation in different tissues including the vasculature. There is a causal link between adipose tissue (AT) inflammation and obesity-related metabolic complications, such as the development of insulin resistance and subsequently of type 2 diabetes. Intense efforts in the recent years have aimed at dissecting the pathophysiology of AT inflammation. The role of both innate and adaptive immune cells, such as macrophages or cytotoxic T cells in AT inflammation has been demonstrated. Besides these cells, more leukocyte subpopulations have been recently implicated in obesity, including neutrophils and eosinophils, mast cells, natural killer cells or dendritic cells. The involvement of multiple leukocyte subpopulations underlines the complexity of obesity-associated AT inflammation. In this review, we discuss the role of innate immune cells in AT inflammation, obesity and related metabolic disorders.

scholarly journals Macrophages and Dendritic Cells Are Not the Major Source of Pro-Inflammatory Cytokines Upon SARS-CoV-2 Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Marc A. Niles ◽  
Patricia Gogesch ◽  
Stefanie Kronhart ◽  
Samira Ortega Iannazzo ◽  
Georg Kochs ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Influenza A ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
M2 Macrophages ◽  
Myeloid Dendritic Cells ◽  
M1 And M2 Macrophages ◽  
Pro Inflammatory Cytokines

The exact role of innate immune cells upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their contribution to the formation of the corona virus-induced disease (COVID)-19 associated cytokine storm is not yet fully understood. We show that human in vitro differentiated myeloid dendritic cells (mDC) as well as M1 and M2 macrophages are susceptible to infection with SARS-CoV-2 but are not productively infected. Furthermore, infected mDC, M1-, and M2 macrophages show only slight changes in their activation status. Surprisingly, none of the infected innate immune cells produced the pro-inflammatory cytokines interleukin (IL)−6, tumor necrosis factor (TNF)-α, or interferon (IFN)−α. Moreover, even in co-infection experiments using different stimuli, as well as non-influenza (non-flu) or influenza A (flu) viruses, only very minor IL-6 production was induced. In summary, we conclude that mDC and macrophages are unlikely the source of the first wave of cytokines upon infection with SARS-CoV-2.

scholarly journals Zika virus encephalitis in immunocompetent mice is dominated by innate immune cells and does not require T or B cells

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Emina Hayashida ◽  
Zheng Lung Ling ◽  
Thomas M. Ashhurst ◽  
Barney Viengkhou ◽  
So Ri Jung ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Immune Cells ◽  
Zika Virus ◽  
Innate Immune ◽  
Wild Type ◽  
Adaptive Immune ◽  
Intracranial Infection ◽  
Adaptive Immune Cells ◽  
Immunocompetent Mice

Abstract Background Until the end of the twentieth century, Zika virus (ZIKV) was thought to cause a mostly mild, self-limiting disease in humans. However, as the geographic distribution of ZIKV has shifted, so too has its pathogenicity. Modern-day ZIKV infection is now known to cause encephalitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome in otherwise healthy adults. Nevertheless, the underlying pathogenetic mechanisms responsible for this shift in virulence remain unclear. Methods Here, we investigated the contribution of the innate versus the adaptive immune response using a new mouse model involving intracranial infection of adult immunocompetent mice with a moderately low dose of ZIKV MR766. To determine the contribution of type I interferons (IFN-Is) and adaptive immune cells, we also studied mice deficient for the IFN-I receptor 1 (Ifnar1−/−) and recombination-activating gene 1 (Rag1−/−). Results We show that intracranial infection with ZIKV resulted in lethal encephalitis. In wild-type mice, ZIKV remained restricted predominantly to the central nervous system (CNS) and infected neurons, whereas astrocytes and microglia were spared. Histological and molecular analysis revealed prominent activation of resident microglia and infiltrating monocytes that were accompanied by an expression of pro-inflammatory cytokines. The disease was independent of T and B cells. Importantly, unlike peripheral infection, IFN-Is modulated but did not protect from infection and lethal disease. Lack of IFN-I signaling resulted in spread of the virus, generalized inflammatory changes, and accelerated disease onset. Conclusions Using intracranial infection of immunocompetent wild-type mice with ZIKV, we demonstrate that in contrast to the peripheral immune system, the CNS is susceptible to infection and responds to ZIKV by initiating an antiviral immune response. This response is dominated by resident microglia and infiltrating monocytes and macrophages but does not require T or B cells. Unlike in the periphery, IFN-Is in the CNS cannot prevent the establishment of infection. Our findings show that ZIKV encephalitis in mice is dependent on the innate immune response, and adaptive immune cells play at most a minor role in disease pathogenesis.

Abstract 073: Expression of Axl in Innate Immune Cells Contributes to Kidney Dysfunction and Onset of Hypertension

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Vyacheslav A Korshunov ◽  
Kyung A Ko ◽  
Deanne Mickelsen ◽  
Ronald W Wood ◽  
Sri N Batchu
Keyword(s):  
Renal Artery ◽  
Immune Cells ◽  
Resistive Index ◽  
Innate Immune ◽  
Initial Increase ◽  
Innate Immune Cells ◽  
Kidney Dysfunction ◽  
Double Knockout ◽  
Adaptive Immune Cells

Introduction: We previously reported that expression of the receptor tyrosine kinase Axl in hematopoietic cells is critical for kidney dysfunction in early hypertension. Here we investigated the role of Axl expression in innate immune cells in deoxycorticosterone acetate (DOCA)-salt induced hypertension. Methods and Results: RAG1-/- mice lack adaptive immune cells and displayed the same (~25 mmHg) increase in systolic blood pressure (BP) as C57BL/6J mice after 1 week of DOCA-salt. While in metabolic cages RAG1-/- drank more (14.3±0.9 mL) than C57BL/6J mice (10.6±2.5 mL) per day after 1 week of DOCA-salt. Ultrasound imaging confirmed that RAG1-/- had ~20 % larger kidneys vs. C57BL/6J mice after DOCA-salt. RAG1-/- kidneys accumulated 2 times more fluid (2.8±0.1 %) compared to C57BL/6J mice (1.4±0.5 %) after DOCA-salt. Flow cytometry on kidneys from RAG1-/- confirmed absence of T and B lymphocytes, while DOCA-salt increased presence of macrophages (1.1±0.3 x10 9 ) compared to C57BL/6J mice (0.6±0.1 x10 9 ). We successfully generated Axl/RAG1 double knockout mice and subjected the littermates to 1 week of DOCA-salt. Increases in systolic BP were the same in Axl/RAG1+/+ and Axl/RAG1-/- littermate mice. No differences were found in kidney volumes between the Axl/RAG1 genotypes as well. However, 24 hrs excretion volumes increased in Axl/RAG1-/- (50±6 %) compared to Axl/RAG1+/+ (31±6 %) littermates. Finally, renal artery blood flow velocity (611±52 mm/s) and resistive index (0.62±0.03) were reduced in Axl/RAG1+/+ but not in Axl/RAG1-/- mice (665±45 mm/s and 0.68±0.01, respectively) when compared to their controls. Conclusions: Our findings suggest that mice lacking lymphocytes compensate by increasing kidney macrophages that contribute to initial increase in BP. Depletion of Axl in innate immune cells partially reverses kidney dysfunction by improving renal artery function in early hypertension.

Sign in / Sign up

Export Citation Format

Share Document