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Author: Wei-Jen Chua Yankelevich Publisher: ISBN: Category : Electronic dissertations Languages : en Pages : 170
Book Description
MHC-related protein 1 (MR1) is the non-classical MHC class I molecule that is responsible for the selection and development of mucosal-associated invariant T (MAIT) cells. The Mr1 gene is monomorphic and highly conserved among mammals, while MAIT cells display an invariant V[alpha] paired with limited V[beta] TCR chains. Despite the ubiquitous detection of MR1 transcripts and intracellular protein, it has been difficult to detect expression of endogenous MR1 on the plasma membrane resulting in the long-pending question of the physiological role of endogenous MR1. Additionally, although previous studies have implicated antigen presentation by MR1to MAIT cells in antibacterial immunity, the mechanism remains undefined. To unveil the physiological role of MR1 and MAIT cells in the immune system, two main approaches were taken in this dissertation: generating new monoclonal antibodies (mAbs) against mouse MR1 to facilitate the detection of endogenous MR1, and establishing in vivo and in vitro models to study MAIT cell responses to microbes. Employing the new mAbs, endogenous MR1 was found to be transiently expressed on the cell surface. More specifically, under basal conditions, low levels of endogenous MR1 could be stabilized at the cell surface by a unique mAb in a functional conformation that activates MAIT cells. In addition, the new mAbs also helped to identify double positive thymocytes, macrophages, and DCs as potential APCs for MAIT cell development and activation. To further probe the function of MR1 and MAIT cells, MAIT cell-deficient mice (as a result of MR1 deficiency) were subjected to bacterial or viral infection as well as a chemical-induced colonic injury. While MR1-restricted MAIT cells were found not to be required for the clearance of the infections of uropathogenic Escherichia coli and West Nile virus, they played a non-redundant role in protective immunity against the infection of Mycobacterium bovis BCG. Taking advantage of an in vitro co-culture assay, MAIT cells were found to inhibit the intracellular mycobacterial growth in macrophages. The antibacterial activity was dependent on the MR1 selection during development, an IL-12/23p40 signal, and IFN-[gamma] secretion. MR1 deficiency also resulted in the lack of proper epithelial regeneration in response to colonic injury. Collectively, research in this dissertation has provided evidence that MR1-restricted MAIT cells play a unique role in the immune system, during both homeostasis and infection.
Author: Wei-Jen Chua Yankelevich Publisher: ISBN: Category : Electronic dissertations Languages : en Pages : 170
Book Description
MHC-related protein 1 (MR1) is the non-classical MHC class I molecule that is responsible for the selection and development of mucosal-associated invariant T (MAIT) cells. The Mr1 gene is monomorphic and highly conserved among mammals, while MAIT cells display an invariant V[alpha] paired with limited V[beta] TCR chains. Despite the ubiquitous detection of MR1 transcripts and intracellular protein, it has been difficult to detect expression of endogenous MR1 on the plasma membrane resulting in the long-pending question of the physiological role of endogenous MR1. Additionally, although previous studies have implicated antigen presentation by MR1to MAIT cells in antibacterial immunity, the mechanism remains undefined. To unveil the physiological role of MR1 and MAIT cells in the immune system, two main approaches were taken in this dissertation: generating new monoclonal antibodies (mAbs) against mouse MR1 to facilitate the detection of endogenous MR1, and establishing in vivo and in vitro models to study MAIT cell responses to microbes. Employing the new mAbs, endogenous MR1 was found to be transiently expressed on the cell surface. More specifically, under basal conditions, low levels of endogenous MR1 could be stabilized at the cell surface by a unique mAb in a functional conformation that activates MAIT cells. In addition, the new mAbs also helped to identify double positive thymocytes, macrophages, and DCs as potential APCs for MAIT cell development and activation. To further probe the function of MR1 and MAIT cells, MAIT cell-deficient mice (as a result of MR1 deficiency) were subjected to bacterial or viral infection as well as a chemical-induced colonic injury. While MR1-restricted MAIT cells were found not to be required for the clearance of the infections of uropathogenic Escherichia coli and West Nile virus, they played a non-redundant role in protective immunity against the infection of Mycobacterium bovis BCG. Taking advantage of an in vitro co-culture assay, MAIT cells were found to inhibit the intracellular mycobacterial growth in macrophages. The antibacterial activity was dependent on the MR1 selection during development, an IL-12/23p40 signal, and IFN-[gamma] secretion. MR1 deficiency also resulted in the lack of proper epithelial regeneration in response to colonic injury. Collectively, research in this dissertation has provided evidence that MR1-restricted MAIT cells play a unique role in the immune system, during both homeostasis and infection.
Author: Kenneth Murphy Publisher: Garland Science ISBN: 9780815344575 Category : Medical Languages : en Pages :
Book Description
The Janeway's Immunobiology CD-ROM, Immunobiology Interactive, is included with each book, and can be purchased separately. It contains animations and videos with voiceover narration, as well as the figures from the text for presentation purposes.
Author: Chloe Knights Slichter Publisher: ISBN: Category : Languages : en Pages : 107
Book Description
Mucosal-associated invariant T (MAIT) cells are a semi-invariant T cell subset that are located in blood, liver and mucosal tissues. When activated MAIT cells display potent effector functions including secretion of secretion of pro-inflammatory cytokines such as interferon-[gamma] (IFN[gamma]) and tumor-necrosis factor alpha (TNF[alpha]) and lysis of bacterially-infected cells through granzyme B. MAIT cells recognize bacterial-derived metabolites, from commensal and pathogenic bacteria, via their semi-invariant T cell receptor (TCR) in the context of the MHC class I related molecule MR1. How MAIT cells distinguish between commensal and pathogenic bacteria is unknown. MAIT cell frequency and function is decreased in the blood in the chronic phase of HIV, HCV, and tuberculosis infection and during these infections MAIT cells express inhibitory receptors. Whether MAIT cells are activated during the acute stage of infection and how MAIT cell responses are turned off is unclear. Here, we address basic questions regarding MAIT cell activation and function during inflammatory disease states: 1) how MAIT cells distinguish between pathogenic and commensal antigen, 2) MAIT functional responses during acute viral infection and 3) how the MAIT cell response is turned off. We demonstrate that a TCR signal alone is not sufficient for sustained MAIT cell effector function, but rather a TCR + cytokine signal is necessary for MAIT cell activation. We propose that this unique control of effector function allows MAIT cells to respond to the same TCR signal (commensal or pathogen derived) in a dichotomous and situation-specific manner. Using an SIV model of infection, we demonstrate that MAIT cells at mucosal sites undergo rapid activation, and acquire effector functions such as expression of tumor-necrosis factor alpha (TNF[alpha]) and granzyme B. In contrast, MAIT cells in the periphery display an early loss of cytokines important for barrier immunity, such as IL-17 and IL-22. These data suggest that MAIT cells become activated early in the mucosa after infection and may play an important role in mucosal homeostasis. Lastly, we interrogate MAIT cell function and transcriptional profiles in inflamed mucosal tissue to address how the MAIT cell response is turned off. We find distinct patterns of inhibitory transcripts by MAIT cells within the inflamed mucosa, including high expression of the inhibitory receptor cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and that cytokine signals alone are sufficient for expression of CTLA-4. Together, our data highlight MAIT cells as important effector cells located at the site of pathogen entry, and begin to elucidate the mechanisms of MAIT cell regulation during inflammatory disease states.
Author: Zlatko Dembic Publisher: Academic Press ISBN: 0124200109 Category : Medical Languages : en Pages : 323
Book Description
The Cytokines of the Immune System catalogs cytokines and links them to physiology and pathology, providing a welcome and hugely timely tool for scientists in all related fields. In cataloguing cytokines, it lists their potential for therapeutic use, links them to disease treatments needing further research and development, and shows their utility for learning about the immune system. This book offers a new approach in the study of cytokines by combining detailed guidebook-style cytokine description, disease linking, and presentation of immunologic roles. Supplies new ideas for basic and clinical research Provides cytokine descriptions in a guidebook-style, cataloging the origins, structures, functions, receptors, disease-linkage, and therapeutic potentials Offers a textbook-style view on the immune system with the immunologic role of each cytokine
Author: Julia D. Berkson Publisher: ISBN: Category : Languages : en Pages : 71
Book Description
Mucosal-associated invariant T (MAIT) cells are a class of unconventional T cells that are defined by a limited T cell receptor (TCR) repertoire that recognize microbial riboflavin-derivative antigens presented by the major histocompatibility complex (MHC) class I-like protein, MR1. Importantly, commensal species of bacteria and yeast in a healthy microbiome generate these metabolite MAIT antigens. Thus, MAIT cells are likely mediators of commensal-specific interactions due to their broad antigen recognition, tissue location and abundance. However, since in vivo characterization of MAIT cells has been minimal, their role in human mucosal tissues is still poorly understood. For example, it is not clear whether functional MR1 is expressed in healthy mucosal tissues and if so, by what classes of immune cells. In this thesis, I use flow cytometric analysis to characterize MAIT cells and assess functional MR1 expression within colonic biopsies and peripheral blood samples from healthy donors. I show extensive MR1 expression among multiple colonic-resident immune cells including antigen-presenting cells and T cells. MAIT cells presented an activated phenotype within the colon with heightened expression of activation markers among the tissue-resident immune cell population. These data suggest that MAIT cells may be continually responding to the microbiota in barrier sites. In addition to their role in normal tissue homeostasis, MAIT cells acquire potent effector function in response to proinflammatory signals, which synergize with a TCR signal. This raises the question how MAIT cells are regulated within inflamed tissues where they presumably would be receiving both of these signals. To address this, I examined the transcriptome of MAIT cells from blood and oral mucosal tissues and found that tissue MAIT cells express an immunoregulatory gene signature, which includes expression of the inhibitory receptor CTLA-4. Further, I define the requirements for surface CTLA-4 protein expression on MAIT cells and demonstrate that inflammatory cytokines are sufficient to elicit and maintain CTLA-4 protein expression on the MAIT cell surface in the absence of a TCR signal. Therefore, control of CTLA-4 expression is fundamentally different from conventional T cells, which require a TCR signal. This mechanism may serve to limit cell-mediated tissue damage in response to commensal antigen within inflamed tissues. Together, this work contributes valuable ex vivo and mechanistic insight into human MAIT cell immunoregulation within healthy and inflamed mucosal tissues.
Author: Jerzy K. Kulski Publisher: MDPI ISBN: 3039280724 Category : Science Languages : en Pages : 374
Book Description
The major histocompatibility complex (MHC) is a highly polymorphic and diverse multigene locus in all jawed vertebrate species that has an integral role in adaptive/innate immune systems, transplantation, and infectious and autoimmune diseases. The MHC supra-locus in mammalian vertebrates is usually partitioned into three distinct regions, known as classes I, II, and III, which, to varying extents, can be found conserved in nonmammalian jawed vertebrates, such as bony fish, amphibians, and bird lineages. The MHC gene region is characterized particularly by the expression of class I and class II glycoproteins that bind peptides derived from intracellular or extracellular antigens to circulating T-cells. While this expressed antigenic specificity remains the predominant interest with respect to MHC function and polymorphism in a population, a broader concept has emerged that examines the MHC as a multifunctional polymorphic controller that facilitates and regulates genome diversity with a much greater array of functions and effects than just MHC-restricted antigen recognition. This volume of 19 reprints presented by various experts and collected from the Special Issue of Cells on “MHC in Health and Disease” covers a broad range of topics on the genomic diversity of the MHC regulatory system in various vertebrate species, including MHC class I, II, and III genes; innate and adaptive immunity; neurology; transplantation; haplotypes; infectious and autoimmune diseases; fecundity; conservation; allelic lineages; and evolution. Taken together, these articles demonstrate the immense complexity and diversity of the MHC structure and function within and between different vertebrate species.
Author: Publisher: Academic Press ISBN: 0080921523 Category : Medical Languages : en Pages : 3161
Book Description
Encyclopedia of Immunobiology, Five Volume Set provides the largest integrated source of immunological knowledge currently available. It consists of broad ranging, validated summaries on all of the major topics in the field as written by a team of leading experts. The large number of topics covered is relevant to a wide range of scientists working on experimental and clinical immunology, microbiology, biochemistry, genetics, veterinary science, physiology, and hematology. The book is built in thematic sections that allow readers to rapidly navigate around related content. Specific sections focus on basic, applied, and clinical immunology. The structure of each section helps readers from a range of backgrounds gain important understanding of the subject. Contains tables, pictures, and multimedia features that enhance the learning process In-depth coverage allows readers from a range of backgrounds to benefit from the material Provides handy cross-referencing between articles to improve readability, including easy access from portable devices
Author: Robert G. Urban Publisher: Springer ISBN: Category : Juvenile Nonfiction Languages : en Pages : 320
Book Description
3 nant expression systems have been used to make MHC molecules con taining a single peptide of interest. To date, fifteen single peptide class I structures (incorporating three different HLA and two different H-2 allotypes/isotypes) and four additional class II structures (two single peptide complexes and two superantigen complexes) have been reported. These advances have enabled us to study the atomic detail of antigen presentation and the general mechanisms behind peptide binding, and begin to construct models of T cell recognition. Another area of research which has exploded over the past five years has been the identification of MHC-associated peptides. There are several methods one can use to determine the sequence identity of MHC restricted peptides. Historically, the most successful technique, albeit crude and encumbered with serious limitations, has been the use of overlapping synthetic peptides and T cell clones. Unfortunately, this method absolutely requires: (i) knowledge of the target antigen; (ii) availability of T cell clones; and (iii) a relatively short overall length for the target source protein, such that a set of overlapping pep tides can be affordably synthesized. Briefly, the entire sequence of the tar get protein is chemically synthesized using overlapping peptides which are then screened for biological activity using standard T cell presen tation assays. Despite its limitations, this method was used to identify the first immunodominant epitopes reported in the literature and con tinues to be used successfully today.
Author: Wei-Jen Chua Yankelevich
Author: Wei-Jen Chua Yankelevich
Author: Kenneth Murphy
Author: Chloe Knights Slichter
Author: Zlatko Dembic
Author: Julia D. Berkson
Author: Jerzy K. Kulski
Author: 
Author: Michele Kay Anderson
Author: 
Author: Robert G. Urban