scholarly journals Engineering advanced logic and distributed computing in human CAR immune cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jang Hwan Cho ◽  
Atsushi Okuma ◽  
Katri Sofjan ◽  
Seunghee Lee ◽  
James J. Collins ◽  
...  
Keyword(s):  
Immune Cells ◽  
Communication Channel ◽  
Immune Cell ◽  
Cell Types ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Complex Phenotypes ◽  
Car T ◽  
Different Cell Types ◽  
Multiple Immune Cell

AbstractThe immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.

Cytokine release from innate immune cells: association with diverse membrane trafficking pathways

Blood ◽  
2011 ◽  
Vol 118 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Paige Lacy ◽  
Jennifer L. Stow
Keyword(s):  
Membrane Trafficking ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Cytokine Release ◽  
Research Findings ◽  
Specific Receptors ◽  
Different Cell Types

AbstractCytokines released from innate immune cells play key roles in the regulation of the immune response. These intercellular messengers are the source of soluble regulatory signals that initiate and constrain inflammatory responses to pathogens and injury. Although numerous studies describe detailed signaling pathways induced by cytokines and their specific receptors, there is little information on the mechanisms that control the release of cytokines from different cell types. Indeed, the pathways, molecules, and mechanisms of cytokine release remain a “black box” in immunology. Here, we review research findings and new approaches that have begun to generate information on cytokine trafficking and release by innate immune cells in response to inflammatory or infectious stimuli. Surprisingly complex machinery, multiple organelles, and specialized membrane domains exist in these cells to ensure the selective, temporal, and often polarized release of cytokines in innate immunity.

scholarly journals An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation

2020 ◽  
Vol 126 (11) ◽  
pp. 1565-1589 ◽  
Author(s):  
Lakshmi Arivazhagan ◽  
Henry H. Ruiz ◽  
Robin A. Wilson ◽  
Michaele B. Manigrasso ◽  
Paul F. Gugger ◽  
...  
Keyword(s):  
Physical Activity ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Innate Immune Cells ◽  
Metabolic Perturbation ◽  
Adaptive Immune Cells ◽  
Reduced Physical Activity

The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow–derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type–specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.

scholarly journals Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

2021 ◽  
Vol 14 ◽  
Author(s):  
Elise Liu ◽  
Léa Karpf ◽  
Delphine Bohl
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Immune System ◽  
Frontotemporal Dementia ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Cell Types ◽  
Induced Pluripotent ◽  
Different Cell Types ◽  
Lateral Sclerosis

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

Evidence for B cell maturation but not trained immunity in uninfected infants exposed to hepatitis C virus

Gut ◽  
2020 ◽  
Vol 69 (12) ◽  
pp. 2203-2213 ◽  
Author(s):  
Anton Lutckii ◽  
Benedikt Strunz ◽  
Anton Zhirkov ◽  
Olga Filipovich ◽  
Elena Rukoiatkina ◽  
...  
Keyword(s):  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Cell Maturation ◽  
Innate Immune Cells ◽  
B Cell Maturation ◽  
Exposed Uninfected

ObjectivesVertical transmission of hepatitis C virus (HCV) is rare compared with other chronic viral infections, despite that newborns have an immature, and possibly more susceptible, immune system. It further remains unclear to what extent prenatal and perinatal exposure to HCV affects immune system development in neonates.DesignTo address this, we studied B cells, innate immune cells and soluble factors in a cohort of 62 children that were either unexposed, exposed uninfected or infected with HCV. Forty of these infants were followed longitudinally from birth up until 18 months of age.ResultsAs expected, evidence for B cell maturation was observed with increased age in children, whereas few age-related changes were noticed among innate immune cells. HCV-infected children had a high frequency of HCV-specific IgG-secreting B cells. Such a response was also detected in some exposed but uninfected children but not in uninfected controls. Consistent with this, both HCV-exposed uninfected and HCV-infected infants had evidence of early B cell immune maturation with an increased proportion of IgA-positive plasma cells and upregulated CD40 expression. In contrast, actual HCV viraemia, but not mere exposure, led to alterations within myeloid immune cell populations, natural killer (NK) cells and a distinct soluble factor profile with increased levels of inflammatory cytokines and chemokines.ConclusionOur data reveal that exposure to, and infection with, HCV causes disparate effects on adaptive B cells and innate immune cell such as myeloid cells and NK cells in infants.

scholarly journals Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery

2015 ◽  
Vol 309 (12) ◽  
pp. H2042-H2057 ◽  
Author(s):  
Sanjukta Chakraborty ◽  
Scott D. Zawieja ◽  
Wei Wang ◽  
Yang Lee ◽  
Yuan J. Wang ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Contractile Activity ◽  
Macrophage Polarization ◽  
Lymphatic Vessels ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Lymphatic Function ◽  
Inflammatory Conditions ◽  
Rat Mesentery

Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as LPS. However, the direct mechanisms by which LPS influences the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturbs tissue cytokine/chemokine homeostasis and subsequently influences lymphatic function. We used rats that were intraperitoneally injected with LPS (10 mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This population of monocytes and macrophages established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemoattractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2, and galectin-9. LPS-TLR4-mediated regulation of pAKT, pERK pI-κB, and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus, our data provide the first evidence connecting the dynamic changes in innate immune cells on or near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction.

scholarly journals Elucidating the Innate Immunological Effects of Mild Magnetic Hyperthermia on U87 Human Glioblastoma Cells: An in vitro Study

2021 ◽  
Author(s):  
Stefano Persano ◽  
Francesco Vicini ◽  
Alessandro Poggi ◽  
Jordi Leonardo Castrillo Fernandez ◽  
Giusy Maria Rita Rizzo ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Magnetic Hyperthermia ◽  
Innate Immune ◽  
Target Cells ◽  
Innate Immune Cells ◽  
Glioblastoma Cells ◽  
Mild Hyperthermia ◽  
Wide Range

Cancer immunotherapies are gaining a large popularity and many of them have been approved as standard second-line or in some cases even as first-line treatment for a wide range of cancers. However, immunotherapy has not shown a clinically relevant success in glioblastoma (GBM), principally due to the brain’s “immune-privileged” status and the peculiar tumor microenvironment (TME) of GBM featured by lack of presence of tumor-infiltrating lymphocytes and the establishment of immunosuppressive mechanisms. Emerging evidence has highlighted the key role played by innate immune cells in immunosurveillance and in initiating and driving immune responses against GBM. Immunogenic cell death (ICD) is a promising approach to elicit direct activation of the innate immune system by inducing in target cancer cells the expression of molecular signatures recognized through a repertoire of innate immune cell pattern recognition receptors (PRRs) by effector innate immune cells. Herein, we explored local mild thermal treatment, generated by using ultrasmall (size ~ 17 nm) cubic-shaped iron oxide nanoparticles exposed to an external alternating magnetic field (AMF), to induce ICD in U87 glioblastoma cells. In accordance with what has been previously observed with other types of tumors, we found that mild hyperthermia modulates the immunological profile of U87 glioblastoma cells by inducing stress-associated signals leading to enhanced phagocytosis and killing of U87 cells by macrophages. Finally, we demonstrated that mild magnetic hyperthermia has a modulatory effect on the expression of inhibitory and activating NK cell ligands on target cells. Interestingly, alteration in the expression of NK ligands, caused by mild hyperthermia treatment, in U87 glioblastoma cells, increased their susceptibility to NK cell killing and NK cell functionality. The overall findings demonstrate that mild magnetic hyperthermia stimulates ICD and sensitizes GBM cells to NK-mediated killing by inducing the upregulation of specific stress ligands, providing a novel immunotherapeutic approach for GBM treatment, with potential to synergize with existing NK cell-based therapies thus improving their therapeutic outcomes.

scholarly journals The cell biology of inflammation: From common traits to remarkable immunological adaptations

2020 ◽  
Vol 219 (7) ◽  
Author(s):  
Helen Weavers ◽  
Paul Martin
Keyword(s):  
Innate Immunity ◽  
Cell Division ◽  
Membrane Trafficking ◽  
Immune Cells ◽  
Cell Biology ◽  
Foreign Bodies ◽  
Cell Types ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Starting Point

Tissue damage triggers a rapid and robust inflammatory response in order to clear and repair a wound. Remarkably, many of the cell biology features that underlie the ability of leukocytes to home in to sites of injury and to fight infection—most of which are topics of intensive current research—were originally observed in various weird and wonderful translucent organisms over a century ago by Elie Metchnikoff, the “father of innate immunity,” who is credited with discovering phagocytes in 1882. In this review, we use Metchnikoff’s seminal lectures as a starting point to discuss the tremendous variety of cell biology features that underpin the function of these multitasking immune cells. Some of these are shared by other cell types (including aspects of motility, membrane trafficking, cell division, and death), but others are more unique features of innate immune cells, enabling them to fulfill their specialized functions, such as encapsulation of invading pathogens, cell–cell fusion in response to foreign bodies, and their self-sacrifice as occurs during NETosis.

scholarly journals Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer

2017 ◽  
Vol 114 (39) ◽  
pp. 10455-10460 ◽  
Author(s):  
Keehoon Jung ◽  
Takahiro Heishi ◽  
Joao Incio ◽  
Yuhui Huang ◽  
Elizabeth Y. Beech ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Cell ◽  
Antiangiogenic Therapy ◽  
Innate Immune ◽  
Growth Delay ◽  
Innate Immune Cells ◽  
Tumor Growth Delay ◽  
Anti Vegf

Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1−/− mice), Ly6Chigh monocytes (CCR2−/− mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2–induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2–induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.

scholarly journals Keratinocytes contribute intrinsically to psoriasis upon loss of Tnip1 function

2016 ◽  
Vol 113 (41) ◽  
pp. E6162-E6171 ◽  
Author(s):  
Sirish K. Ippagunta ◽  
Ruchika Gangwar ◽  
David Finkelstein ◽  
Peter Vogel ◽  
Stephane Pelletier ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Process ◽  
Immune Cell ◽  
Genetic Alterations ◽  
Innate Immune ◽  
Negative Regulator ◽  
Specific Gene ◽  
Innate Immune Cells ◽  
Chemokine Production

Psoriasis is a chronic inflammatory skin disease with a clear genetic contribution, characterized by keratinocyte proliferation and immune cell infiltration. Various closely interacting cell types, including innate immune cells, T cells, and keratinocytes, are known to contribute to inflammation. Innate immune cells most likely initiate the inflammatory process by secretion of IL-23. IL-23 mediates expansion of T helper 17 (Th17) cells, whose effector functions, including IL-17A, activate keratinocytes. Keratinocyte activation in turn results in cell proliferation and chemokine expression, the latter of which fuels the inflammatory process through further immune cell recruitment. One question that remains largely unanswered is how genetic susceptibility contributes to this process and, specifically, which cell type causes disease due to psoriasis-specific genetic alterations. Here we describe a mouse model based on the human psoriasis susceptibility locus TNIP1, also referred to as ABIN1, whose gene product is a negative regulator of various inflammatory signaling pathways, including the Toll-like receptor pathway in innate immune cells. We find that Tnip1-deficient mice recapitulate major features of psoriasis on pathological, genomic, and therapeutic levels. Different genetic approaches, including tissue-specific gene deletion and the use of various inflammatory triggers, reveal that Tnip1 controls not only immune cells, but also keratinocyte biology. Loss of Tnip1 in keratinocytes leads to deregulation of IL-17–induced gene expression and exaggerated chemokine production in vitro and overt psoriasis-like inflammation in vivo. Together, the data establish Tnip1 as a critical regulator of IL-17 biology and reveal a causal role of keratinocytes in the pathogenesis of psoriasis.

The role of SLAM family receptors in immune cell signalingThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 832-843 ◽  
Author(s):  
Elena A. Ostrakhovitch ◽  
Shawn S.-C. Li
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Types ◽  
Health And Disease ◽  
Slam Family ◽  
Different Cell Types ◽  
Selection Of

The signaling lymphocyte-activating molecule (SLAM) family immunoreceptors are expressed in a wide array of immune cells, including both T and B lymphocytes. By virtue of their ability to transduce tyrosine phosphorylation signals through the so-called ITSM (immunoreceptor tyrosine-based switch motif) sequences, they play an important part in regulating both innate and adaptive immune responses. The critical role of the SLAM immunoreceptors in mediating normal immune reactions was highlighted in recent findings that SAP, a SLAM-associated protein, modulates the activities of various immune cells through interactions with different members of the SLAM family expressed in these cells. Importantly, mutations or deletions of the sap gene in humans result in the X-linked lymphoproliferative syndrome. In this review, we summarize current knowledge and survey the latest developments in signal transduction events triggered by the activation of SLAM family receptors in different cell types.

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