Posts Tagged ‘T-cell receptor’

Lymphocytes and Innate Immune Response

Curators: Larry H. Bernstein, MD, FCAP,  and Aviva Lev-Ari, PhD, RN



Scientists Shed Light on Key Role of Innate Lymphoid Cells in the Immune Response



Researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have discovered that innate lymphoid cells, early responders of the immune system, are primed at the DNA level for rapid action. [National Institutes of Health]


Scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have found that the development of innate lymphoid cells (ILCs) gradually prepares these cells for rapid response to infection. This work (“Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality”), which appears in Cell, sheds light on the development and function of a cell type that is increasingly recognized as having an important role in the body’s immune defense.

“Up until now, researchers have focused on T cells, another type of immune cell,” said John J. O’Shea, M.D., scientific director of NIAMS and senior author of the paper. “ILCs are coming into the spotlight because they appear to have a critical role in defending the body’s barrier regions, such as the skin, lungs, and gut, where microbes must first pass to make their way into the body.”

The importance of T cells became apparent during the 1980s with the emergence of the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). HIV attacks a certain class of T cells, destroying a person’s immune defenses and leaving him or her susceptible to infection and cancer. Since that time, investigators around the world have identified the distinct functions of T cell subclasses, providing new insights into their roles in host defense and opportunities for novel therapeutic strategies.

ILCs have received less attention, despite their critical role in mounting the innate immune response. Recent work has revealed that ILCs and T cells mirror each other in their subclasses, which are defined by the kinds of cytokines they produce. However, the relationships between the two types of cells have been unclear.

To determine what sets ILCs apart from T cells, Dr. O’Shea’s team looked to the foundation of a cell’s identity—its genetic information, which provides detailed instructions for how a cell functions. Part of what makes each cell type unique is its distinctive pattern of DNA structure and regulatory factors. The combination of a stretch of DNA and a set of regulatory factors can be thought of as a switch; it helps determine whether a gene is turned off or on.

Inactive regions of the DNA molecule are twisted into tight coils, whereas active regions are open and accessible to the cellular machinery that reads the genetic information. The open portions of the genome include genes themselves, as well as many regions that contribute to the regulation of their activities (the switches). The areas of the genome and the factors that control whether or not the information is read, in total, are referred to as the cell’s regulome.

Working in mice, the NIAMS researchers analyzed regions of the genome that control the cytokine genes produced by both ILCs and T cells. They found that each subclass of ILCs is associated with a distinct pattern of accessible regions. These patterns can be viewed as a type of barcode for each subclass. Further experiments showed that ILCs acquire their barcodes in a stepwise manner over the course of cellular development.

Importantly, the analysis showed that the barcodes are in place in ILCs before they encounter infection. This open, accessible configuration surrounding the switches that control cytokine genes may be instrumental in enabling ILCs to launch an assault rapidly upon infection.

In contrast, the researchers found that many of the DNA regions controlling cytokine genes in the mice’s T cells are inaccessible and silenced prior to exposure to a pathogen. But upon infection, T cells adopted barcodes similar to those of their ILC counterparts. This result reflected earlier findings that ILC and T cell subclasses produce similar sets of cytokines, but also revealed differences in how the two cell types control the activities of these key immune response genes.

While the regulatory landscapes of ILCs are primed for a quick defense upon infection, those of T cells are minimally prepared when the pathogen invades. Only following infection are modifications in the landscape made that enable T cells to launch their attack.

“ILCs and T cells appear very different, but in the end, the way they control key responses is amazingly similar,” said Han-Yu Shih, Ph.D., a postdoctoral fellow at NIAMS and first author of the paper. “ILCs were discovered less than a decade ago, but the parallels between them and T cells will enable us to more quickly understand how they work and to develop ways to enhance or inhibit their function in treating a variety of immune and inflammatory diseases.”


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Reporter: Aviva Lev-Ari, PhD, RN




Trypanosoma cruzi Trans-Sialidase Initiates a Program Independent of the Transcription Factors RORγt and Ahr that Leads to IL-17 Production by Activated B Cells

Researchers identified B cells as a major source of rapid, innate-like production of interleukin 17 (IL-17) in vivo in response to infection with Trypanosoma cruzi. IL-17+ B cells had a plasmablast phenotype, outnumbered cells of the TH17 subset of helper T cells and were required for an optimal response to this pathogen. [Nat Immunol] Abstract

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Autoimmune Pancreatitis in MRL/Mp Mice Is a T Cell-Mediated Disease Responsive to Cyclosporine A and Rapamycin Treatment

The authors report that blockage of CTLA-4 in MRL/Mp mice suppressed regulatory T cell function and raised the effector T cell response with subsequent histomorphological organ destruction, indicating that autoimmune pancreatitis is a T cell-driven disease. Using an established histopathological score, they found that dexamethasone, cyclosporine A and rapamycin, but less so azathioprine, reduced pancreatic damage. [Gut] Abstract

Excessive Th1 Responses Due to the Absence of TGF-β Signaling Cause Autoimmune Diabetes and Dysregulated Treg Cell Homeostasis

TGF-β signaling in T cells is critical for peripheral T-cell tolerance by regulating effector CD4+ T helper (Th) cell differentiation. However, it is still controversial to what extent TGF-β signaling in Foxp3+ regulatory T (Treg) cells contributes to immune homeostasis. Researchers showed that abrogation of TGF-β signaling in thymic T cells led to rapid type 1 diabetes development in NOD mice transgenic for the BDC2.5 T-cell receptor. [Proc Natl Acad Sci USA] Abstract

Inhibition of PDE4B Suppresses Inflammation by Increasing Expression of the Deubiquitinase CYLD

The deubiquitinase CYLD acts as a key negative regulator to tightly control overactive inflammation. Most anti-inflammatory strategies have focused on directly targeting the positive regulator, which often results in significant side effects such as suppression of the host defense response. Researchers showed that inhibition of phosphodiesterase 4B (PDE4B) markedly enhances upregulation of CYLD expression in response to bacteria, thereby suggesting that PDE4B acts as a negative regulator for CYLD. [Nat Commun] Abstract | Press Release

Regulatory T Cells Prevent Plaque Disruption in Apolipoprotein E-Knockout Mice

Investigators report that adoptive transfer of regulatory T cells dose-dependently changed plaque composition to a stable plaque phenotype and lowered the incidence of plaque disruption in apolipoprotein E-knockout mice. The major mechanisms involved reduced expression of inflammatory cytokines and matrix metalloproteinase (MMP)-2 and MMP-9, and enhanced expression of P4Hα1 in the carotid plaque. [Int J Cardiol] Abstract

GARP-TGF-β Complexes Negatively Regulate Regulatory T Cell Development and Maintenance of Peripheral CD4+ T Cells In Vivo

Researchers address the role of Glycoprotein A Repetitions Predominant (GARP) in regulating regulatory T cells and conventional T cell development and immune suppression in vivo using a transgenic mouse expressing GARP on all T cells. They found that, despite forced expression of GARP on all T cells, stimulation through the TCR was required for efficient localization of GARP to the cell surface. [J Immunol] Abstract

Fine-Tuning of Regulatory T Cell Function: The Role of Calcium Signals and Naive Regulatory T Cells for Regulatory T Cell Deficiency in Multiple Sclerosis

As regulatory T cells (Tregs) counteract the sustained elevation of intracellular calcium, which is indispensable for full activation of conventional T cells (Tcons), the authors hypothesized that interference with this pathway might prompt multiple sclerosis-related Treg dysfunction. Using single-cell live imaging, they observed that Tregs rapidly reduce Ca2+ influx and downstream signals in Tcons upon cell contact, yet differ in their potency to efficiently suppress several target cells at the same time. [J Immunol] Abstract

Systems Model of T Cell Receptor Proximal Signaling Reveals Emergent Ultrasensitivity

Researchers used a systems model to show that signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual T cell antigen receptors. Importantly, this switch-like response is an emergent property, so that removal of multiple immunoreceptor tyrosine-based activation motifs, sequential phosphorylation, or differential affinities abolishes the switch. [PLoS Comput Biol]

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Decreased Regulatory T-Cells and CD4+/CD8+ Ratio Correlate with Disease Onset and Progression in Patients with Generalized Vitiligo

Scientists evaluated CD4+/CD8+ ratio and CD4+CD25hiFoxP3+ regulatory T cells (Tregs) in Generalized Vitiligo (GV) patients with reference to their effect on disease onset and progression. Flow cytometry was used for determination of CD4+/CD8+ ratio and Tregs in 82 patients and 50 controls. CD8+ T-cell counts were significantly higher in GV patients as compared to controls. [Pigment Cell Melanoma Res] Abstract

Sex Bias in Experimental Immune-Mediated, Drug-Induced Liver Injury in BALB/c Mice: Suggested Roles for Tregs, Estrogen, and IL-6

Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, researchers investigated their role in a mouse model of immune-mediated drug-induced liver injury. [PLoS One] Full Article

The Hedgehog Receptor Patched1 in T Cells Is Dispensable for Adaptive Immunity in Mice

Hedgehog (Hh) signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue, researchers made use of conditional knock-out mice in which the Hh receptor Patched1 is inactivated in the T cell lineage. [PLoS One] Full Article



Modulating T Regulatory Cells in Cancer: How Close Are We?

The authors provide a historical perspective of the discovery of regulatory T cells (Tregs), followed by a summary of the existing literature on the role of Tregs in malignancy. [Immunol Cell Biol] Abstract

Importance of Reverse Signaling of the TNF Superfamily in Immune Regulation

F-related ligands (with the exception of lymphotoxin-α) are synthesized as type II transmembrane proteins, though many of them also have soluble forms. An increasing number of publications report that these ‘ligands’ behave as receptors, activating intracellular signaling pathways when interacting with cognate ‘receptors’ or agonistic antibodies. [Expert Rev Clin Immunol] Abstract

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Immunotherapies against Cancer: German Cancer Research Center to Broaden Strategic Alliance with Bayer HealthCare

The German Cancer Research Center and Bayer HealthCare will extend their successful strategic research alliance in search of novel cancer therapeutics by focusing their activities also on the field of immunotherapy. [German Cancer Research Center] Press Release

Pitt Team Gets $5 Million National Institutes of Health Grant to Make Vaccine Component that Stimulates TB-Fighting T-Cells

Researchers at the University of Pittsburgh School of Medicine have received a $5 million federal grant to develop a vaccine ingredient that can generate the type of immune response needed to protect against tuberculosis (TB) infection. [UPMC/University of Pittsburgh Schools of the Health Sciences] Press Release

T Cell Biology Pioneer Allison Wins First AACR Honor for Cancer Immunology

The scientist whose discoveries led to the first drug approved for metastatic melanoma by “treating the immune system, not the cancer,” also is the first to receive the AACR-CRI Lloyd J. Old Award in Cancer Immunology. James Allison, Ph.D., professor and chair of The University of Texas MD Anderson Cancer Center Department of Immunology, was honored at the AACR Annual Meeting 2013 in Washington, D.C. [The University of Texas MD Anderson Cancer Center] Press Release

Immune Therapy from Austria Receives Orphan Drug Designation from European Medicines Agency

The European Medicines Agency recently awarded the Austrian biotech company Activartis an Orphan Drug Designation for its innovative Cancer Immune Therapy AV0113. The Orphan Drug Designation applies specifically to the use of AV0113 for the treatment of glioma, a type of brain tumor, which afflicts around one in 10.000 people in the EU. [Activartis Biotech GmbH] Press Release

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October 23-25, 2013

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