Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease

Cytokines activate or inhibit immune cell behavior and are thus integral to all immune responses. IL-1α and IL-1β are powerful apical cytokines that instigate multiple downstream processes to affect both innate and adaptive immunity. Multiple studies show that IL-1β is typically activated in macrophages after inflammasome sensing of infection or danger, leading to caspase-1 processing of IL-1β and its release. However, many alternative mechanisms activate IL-1α and IL-1β in atypical cell types, and IL-1 function is also important for homeostatic processes that maintain a physiological state. This review focuses on the less studied, yet arguably more interesting biology of IL-1. We detail the production by, and effects of IL-1 on specific innate and adaptive immune cells, report how IL-1 is required for barrier function at multiple sites, and discuss how perturbation of IL-1 pathways can drive disease. Thus, although IL-1 is primarily studied for driving inflammation after release from macrophages, it is clear that it has a multifaceted role that extends far beyond this, with various unconventional effects of IL-1 vital for health. However, much is still unknown, and a detailed understanding of cell-type and context-dependent actions of IL-1 is required to truly understand this enigmatic cytokine, and safely deploy therapeutics for the betterment of human health.

Download Full-text

Single-cell transcriptomics to explore the immune system in health and disease

Science ◽

10.1126/science.aan6828 ◽

2017 ◽

Vol 358 (6359) ◽

pp. 58-63 ◽

Cited By ~ 198

Author(s):

Michael J. T. Stubbington ◽

Orit Rozenblatt-Rosen ◽

Aviv Regev ◽

Sarah A. Teichmann

Keyword(s):

Immune System ◽

Single Cell ◽

Immune Cells ◽

Cell Types ◽

Massively Parallel ◽

Antigen Receptors ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Health And Disease ◽

Multiple Cell

The immune system varies in cell types, states, and locations. The complex networks, interactions, and responses of immune cells produce diverse cellular ecosystems composed of multiple cell types, accompanied by genetic diversity in antigen receptors. Within this ecosystem, innate and adaptive immune cells maintain and protect tissue function, integrity, and homeostasis upon changes in functional demands and diverse insults. Characterizing this inherent complexity requires studies at single-cell resolution. Recent advances such as massively parallel single-cell RNA sequencing and sophisticated computational methods are catalyzing a revolution in our understanding of immunology. Here we provide an overview of the state of single-cell genomics methods and an outlook on the use of single-cell techniques to decipher the adaptive and innate components of immunity.

Download Full-text

P042 CHARACTERIZATION OF INNATE AND ADAPTIVE IMMUNE CELLS INVOLVED IN THE FOREIGN BODY REACTION TO POLYPROPYLENE MESHES IN THE HUMAN ABDOMEN

British Journal of Surgery ◽

10.1093/bjs/znab395.039 ◽

2021 ◽

Vol 108 (Supplement_8) ◽

Author(s):

Axel Dievernich ◽

Pascal Achenbach ◽

Luke Davies ◽

Uwe Klinge

Keyword(s):

T Cells ◽

Foreign Body ◽

Immune Cells ◽

Foreign Body Reaction ◽

Immune Cell ◽

Cell Types ◽

Specific Cell ◽

T Helper ◽

Adaptive Immune ◽

Adaptive Immune Cells

Abstract Aim Polypropylene (PP) mesh is widely used to reinforce tissues. The foreign body reaction (FBR) to the implant is dominated by innate immune cells, especially macrophages. However, considerable numbers of adaptive immune cells have also been regularly observed, which appear to play a crucial role in the long-term host response. This study investigated the FBR to seven human PP meshes, which were removed from the abdomen for recurrence after a median of one year. Material and Methods Using immunofluorescence microscopy and distance maps, the FBR was spatially analyzed for various innate (e.g., CD68+ macrophages, CD56+ NK) and adaptive immune cells (CD3+ T, CD4+ T-helper, CD8+ cytotoxic, FoxP3+ T-regulatory, CD20+ B) as well as “conventional” immune cells (defined as cells expressing their specific immune cell marker without co-expressing CD68). Results T-helper cells (19%) and regulatory T-cells (25%) were present at comparable rates to macrophages, and clustered significantly toward the mesh fibers. For all cell types the lowest proportions of “conventional” cells (< 60%) were observed at the mesh–tissue interface, but increased considerably at about 50–100 µm, indicating reduced stimulation with rising distance to the mesh fibers. Conclusions Both innate and adaptive immune cells participate in the chronic FBR to PP meshes with T cells and macrophages being the predominant cell types, respectively. Furthermore, many cells present a “hybrid” pattern near the mesh fibers. The complexity of the local immune reaction may explain why approaches focusing on specific cell types have not been very successful in reducing the chronic FBR.

Download Full-text

Characterization of innate and adaptive immune cells involved in the foreign body reaction to polypropylene meshes in the human abdomen

Hernia ◽

10.1007/s10029-021-02396-7 ◽

2021 ◽

Author(s):

A. Dievernich ◽

P. Achenbach ◽

L. Davies ◽

U. Klinge

Keyword(s):

T Cells ◽

Foreign Body ◽

Immune Cells ◽

Foreign Body Reaction ◽

Immune Cell ◽

Cell Types ◽

Specific Cell ◽

T Helper ◽

Adaptive Immune ◽

Adaptive Immune Cells

Abstract Background Polypropylene (PP) mesh is widely used to reinforce tissues. The foreign body reaction (FBR) to the implant is dominated by innate immune cells, especially macrophages. However, considerable numbers of adaptive immune cells, namely T cells, have also been regularly observed, which appear to play a crucial role in the long-term host response. Methods This study investigated the FBR to seven human PP meshes, which were removed from the abdomen for recurrence after a median of one year. Using immunofluorescence microscopy, the FBR was examined for various innate (CD11b+ myeloid, CD68+ macrophages, CD56+ NK) and adaptive immune cells (CD3+ T, CD4+ T-helper, CD8+ cytotoxic, FoxP3+ T-regulatory, CD20+ B) as well as “conventional” immune cells (defined as cells expressing their specific immune cell marker without co-expressing CD68). Results T-helper cells (19%) and regulatory T-cells (25%) were present at comparable rates to macrophages, and clustered significantly toward the mesh fibers. For all cell types the lowest proportions of “conventional” cells (< 60%) were observed at the mesh–tissue interface, but increased considerably at about 50–100 µm, indicating reduced stimulation with rising distance to the mesh fibers. Conclusion Both innate and adaptive immune cells participate in the chronic FBR to PP meshes with T cells and macrophages being the predominant cell types, respectively. In concordance with the previous data, many cells presented a “hybrid” pattern near the mesh fibers. The complexity of the immune reaction seen within the foreign body granuloma may explain why approaches focusing on specific cell types have not been very successful in reducing the chronic FBR.

Download Full-text

Fibroblasts Influence the Efficacy, Resistance, and Future Use of Vaccines and Immunotherapy in Cancer Treatment

Vaccines ◽

10.3390/vaccines9060634 ◽

2021 ◽

Vol 9 (6) ◽

pp. 634

Author(s):

Bailee H. Sliker ◽

Paul M. Campbell

Keyword(s):

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Fibroblast Activation Protein ◽

Cancer Associated Fibroblasts ◽

Cell Type ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

New Research ◽

Tumor Types

Tumors are composed of not only epithelial cells but also many other cell types that contribute to the tumor microenvironment (TME). Within this space, cancer-associated fibroblasts (CAFs) are a prominent cell type, and these cells are connected to an increase in tumor progression as well as alteration of the immune landscape present in and around the tumor. This is accomplished in part by their ability to alter the presence of both innate and adaptive immune cells as well as the release of various chemokines and cytokines, together leading to a more immunosuppressive TME. Furthermore, new research implicates CAFs as players in immunotherapy response in many different tumor types, typically by blunting their efficacy. Fibroblast activation protein (FAP) and transforming growth factor β (TGF-β), two major CAF proteins, are associated with the outcome of different immunotherapies and, additionally, have become new targets themselves for immune-based strategies directed at CAFs. This review will focus on CAFs and how they alter the immune landscape within tumors, how this affects response to current immunotherapy treatments, and how immune-based treatments are currently being harnessed to target the CAF population itself.

Download Full-text

Tuning cancer fate: the unremitting role of host immunity

Open Biology ◽

10.1098/rsob.170006 ◽

2017 ◽

Vol 7 (4) ◽

pp. 170006 ◽

Cited By ~ 22

Author(s):

B. Calì ◽

B. Molon ◽

A. Viola

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Tumour Progression ◽

Host Immunity ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Immune Mediated ◽

Immune Cell Subsets ◽

Therapeutic Protocols

Host immunity plays a central and complex role in dictating tumour progression. Solid tumours are commonly infiltrated by a large number of immune cells that dynamically interact with the surrounding microenvironment. At first, innate and adaptive immune cells successfully cooperate to eradicate microcolonies of transformed cells. Concomitantly, surviving tumour clones start to proliferate and harness immune responses by specifically hijacking anti-tumour effector mechanisms and fostering the accumulation of immunosuppressive immune cell subsets at the tumour site. This pliable interplay between immune and malignant cells is a relentless process that has been concisely organized in three different phases: elimination, equilibrium and escape. In this review, we aim to depict the distinct immune cell subsets and immune-mediated responses characterizing the tumour landscape throughout the three interconnected phases. Importantly, the identification of key immune players and molecules involved in the dynamic crosstalk between tumour and immune system has been crucial for the introduction of reliable prognostic factors and effective therapeutic protocols against cancers.

Download Full-text

Nonspecific effects of oral vaccination with live-attenuated Salmonella Typhi strain Ty21a

Science Advances ◽

10.1126/sciadv.aau6849 ◽

2019 ◽

Vol 5 (2) ◽

pp. eaau6849 ◽

Cited By ~ 3

Author(s):

S. H. Pennington ◽

D. M. Ferreira ◽

E. Caamaño-Gutiérrez ◽

J. Reiné ◽

C. Hewitt ◽

...

Keyword(s):

Immune Cell ◽

Salmonella Typhi ◽

Innate Immune ◽

Oral Vaccination ◽

Innate And Adaptive Immunity ◽

Susceptibility To Infection ◽

Adaptive Immune ◽

Nonspecific Effects ◽

All Cause Mortality ◽

Cell Cytokine Production

Epidemiological and immunological evidence suggests that some vaccines can reduce all-cause mortality through nonspecific changes made to innate immune cells. Here, we present the first data to describe the nonspecific immunological impact of oral vaccination with live-attenuated Salmonella Typhi strain Ty21a. We vaccinated healthy adults with Ty21a and assessed aspects of innate and adaptive immunity over the course of 6 months. Changes to monocyte phenotype/function were observed for at least 3 months. Changes to innate and adaptive immune cell cytokine production in response to stimulation with vaccine and unrelated nonvaccine antigens were observed over the 6-month study period. The changes that we have observed could influence susceptibility to infection through altered immune responses mounted to subsequently encountered pathogens. These changes could influence all-cause mortality.

Download Full-text

Total CD3 T Cells Are Necessary and Sufficient to Induce Colitis in Immunodeficient Mice With Dendritic Cell–Specific Deletion of TGFbR2: A Novel IBD Model to Study CD4 and CD8 T-Cell Interaction

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz191 ◽

2019 ◽

Vol 26 (2) ◽

pp. 229-241

Author(s):

Deepa Rana Jamwal ◽

Raji V Marati ◽

Christy A Harrison ◽

Monica T Midura-Kiela ◽

Vanessa R Figliuolo Paz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Dendritic Cell ◽

Cd8 T Cells ◽

Immune Cells ◽

Immune Cell ◽

Immunodeficient Mice ◽

Cell Lineages ◽

Adaptive Immune ◽

Adaptive Immune Cells

Abstract Background Inflammatory bowel disease (IBD) is a multifactorial disorder, with the innate and adaptive immune cells contributing to disease initiation and progression. However, the intricate cross-talk between immune cell lineages remains incompletely understood. The role of CD8+ T cells in IBD pathogenesis has been understudied, largely due to the lack of appropriate models. Methods We previously reported spontaneous colitis in mice with impaired TGFβ signaling due to dendritic cell–specific knockout of TGFbR2 (TGFβR2ΔDC). Here, we demonstrate that crossing TGFβR2ΔDC mice with a Rag1-/- background eliminates all symptoms of colitis and that adoptive transfer of unfractionated CD3+ splenocytes is sufficient to induce progressive colitis in Rag1-/-TGFβR2ΔDC mice. Results Both CD4+ and CD8+ T cells are required for the induction of colitis accompanied by activation of both T-cell lineages and DCs, increased expression of mucosal IFNγ, TNFα, IL6, IL1β, and IL12, and decreased frequencies of CD4+FoxP3+ regulatory T cells. Development of colitis required CD40L expression in CD4+ T cells, and the disease was partially ameliorated by IFNγ neutralization. Conclusions This novel model provides an important tool for studying IBD pathogenesis, in particular the complex interactions among innate and adaptive immune cells in a controlled fashion, and represents a valuable tool for preclinical evaluation of novel therapeutics.

Download Full-text

67 Immunometabolism – emerging concepts and potential applications in livestock

Journal of Animal Science ◽

10.1093/jas/skz258.209 ◽

2019 ◽

Vol 97 (Supplement_3) ◽

pp. 101-101

Author(s):

Barry J Bradford

Keyword(s):

Immune System ◽

Communication Networks ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Whole Body ◽

Phagocytic Cells ◽

Adaptive Immune Cells ◽

Potential Applications ◽

Host Microbe Interactions

Abstract Our understanding of the immune system emerged from the study of disease processes and the communication networks used by various cell types to respond to pathogens. As with many aspects of physiology, this initial view was colored by the techniques available at the time. With technical advances beginning in the 1990, research in sepsis and obesity began to identify critical interactions between the immune system and metabolism. Our current understanding of these interactions is informed by two active but largely distinct research communities. Many in the field of immunology are utilizing cellular metabolism tools to understand mitochondrial function and fuel use in response to activation of innate and adaptive immune cells, especially as these relate to cancer. From another vantage point, many metabolic physiologists are now seeking to understand the importance of tissue-resident immune cells and immune signaling molecules in metabolic homeostasis and pathologies. Beyond human health implications of recent findings, a number of immunometabolism insights have informed our understanding of livestock health. In inflammatory events, phagocytic cells are activated, and the dramatic increase in oxidative metabolism is driven primarily by glucose use. Metabolism of healthy animals is also influenced by secretions from immune cells. Studies in mice indicate that appropriate host/microbe interactions (balancing protection and tolerance) are mediated by a network of immune cell types in the gut, which is critical to both absorptive and barrier functions of the gut. Adipose tissue immune cells regulate lipolytic rate, insulin sensitivity, and perhaps whole-body inflammatory tone. Local immune cell impacts on metabolism of other organs, including the liver and pancreas, are also emerging. Immunity and metabolism are tightly interwoven, and the evolving understanding of these links may enable nutritional or pharmacological strategies to enhance resilience to disease and alter nutrient partitioning in livestock.

Download Full-text

In vitro immunogenicity prediction: bridging between innate and adaptive immunity

Bioanalysis ◽

10.4155/bio-2021-0077 ◽

2021 ◽

Author(s):

Sivan Cohen ◽

Shan Chung

Keyword(s):

Immune Cells ◽

Immune Cell ◽

In Vitro Assays ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Clinical Consequences ◽

Immune Cell Response ◽

Adaptive Immune Systems

Development of antidrug antibodies (ADAs) is an undesirable potential outcome of administration of biotherapeutics and involves the innate and adaptive immune systems. ADAs can have detrimental clinical consequences: they can reduce biotherapeutic efficacy or produce adverse events. Because animal models are considered poor predictors of immunogenicity in humans, in vitro assays with human innate and adaptive immune cells are commonly used alternatives that can reveal cell-mediated unwanted immune responses. Multiple methods have been developed to assess the immune cell response following exposure to biotherapeutics and estimate the potential immunogenicity of biotherapeutics. This review highlights the role of innate and adaptive immune cells as the drivers of immunogenicity and summarizes the use of these cells in assays to predict clinical ADA.

Download Full-text

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.

Biochemistry and Cell Biology ◽

10.1139/o06-191 ◽

2006 ◽

Vol 84 (6) ◽

pp. 832-843 ◽

Cited By ~ 14

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.

Download Full-text