Cd1 And Mr1 Restricted T Cells In Antimicrobial Immunity

Cell-mediated immunity to extracellular and intracellular microbes has been traditionally linked to CD4+ and CD8+ T cells that recognize pathogen-derived peptides in the context of major histocompatibility complex (MHC) class II and class I molecules, respectively. Recent progress in our understanding of early host defense mechanisms has brought ‘unconventional’, innate-like T cells into the spotlight. These are a heterogeneous population of non-MHC-restricted T cells that exhibit ‘memory-like’ properties and mount emergency responses to infection. They may directly detect and destroy infected cells, but are best known for their ability to regulate downstream effector cells including but not limited to conventional T cells. Innate-like T cells include among others CD1-restricted natural killer T (NKT) cells and MR1-restricted mucosa-associated invariant T (MAIT) cells. NKT cells recognize lipid antigens, and MAIT cells were recently demonstrated to respond to microbe-derived vitamin B metabolites. However, much remains to be learned about the antigen specificity range of these cells, their activation mode and their true potentials in immunotherapeutic applications. Like in many other areas of biology, uncertainties and controversies surrounding these cells and some of the experimental models, techniques and reagents employed to study them have brought about excitement and sometimes hot debates. This Special Topic was launched to provide updated reviews on protective and/or pathogenic roles of NKT and MAIT cells during infection. Leading experts discuss current controversies, pressing questions and the challenges that lie ahead for the advancement of this intriguing and rapidly evolving area of immunology. Unlike MHC, CD1 and MR1 display very limited polymorphism. Therefore, NKT and MAIT cells may be considered attractive targets for various diseases in diverse human populations. The potential benefits of NKT cell- and MAIT cell-based vaccination and treatment strategies in infectious diseases is an important subject that is also covered in this Topic.

CD1 and MR1 are major histocompatibility complex (MHC) class I-related proteins that bind and present non-peptide antigens to subsets of T cells with specialized functions. CD1 proteins typically present lipid antigens to CD1-restricted T cells, whereas MR1 presents vitamin B-based ligands and a variety of drugs and drug-like molecules to MR1-restricted T cells. The CD1 family of antigen presenting molecules has been divided into two groups: Group 1 contains CD1a, CD1b and CD1c, and Group 2 contains CD1d. Additionally, CD1e is expressed intracellularly and is involved in the loading of lipid antigens onto Group 1 CD1 proteins. Humans express both Groups 1 and 2 CD1 proteins, whereas mice only express CD1d. Group 1 CD1 proteins present lipid antigens to T cells that generally express diverse T cell receptors (TCRs) and exhibit adaptive-like functions, whereas CD1d presents lipid antigens to subsets of T cells that express either diverse or highly restricted TCRs and exhibit innate-like functions. CD1d-restricted T cells are called natural killer T (NKT) cells, which includes Type I or invariant NKT (iNKT) cells expressing semi-invariant TCRs, and Type II NKT cells expressing more diverse TCRs. CD1-restricted T cells have been implicated in a wide variety of diseases, including cancer, infections, and autoimmune, inflammatory and metabolic diseases. Additionally, NKT cells have been targeted for immunotherapy of disease with ligands such as α-galactosylceramide for iNKT cells, or sulfatide for Type II NKT cells. Like iNKT cells, MR1-restricted T cells express semi-invariant TCRs and display innate-like functions. MR1-restricted T cells, also called mucosal-associated invariant T (MAIT) cells, have been implicated in immune responses against a variety of pathogens such as Mycobacterium tuberculosis, Pseudomonas aeruginosa, Helicobacter pylori, hepatitis C virus and influenza virus. Moreover, these cells contribute to autoimmune and inflammatory diseases, including colitis, rheumatoid arthritis, psoriasis, lupus, and diabetes.

Long-lasting T cell immunity is delivered by an array of individual T lymphocytes expressing clonally distributed and highly specific antigen receptors recognizing an almost infinite number of antigens that might enter in contact with the host. Following antigen-specific priming in lymphnodes, naïve CD4 and CD8 T lymphocytes proliferate generating clones of effector cells that migrate to peripheral tissues and deliver unique antigen-specific effector functions. Moreover, a proportion of these effector lymphocytes survive as memory T cells that can be rapidly mobilized upon new exposure to the same antigen, even years after their primary induction. Innate immune cells play crucial roles in the induction and maintenance of this efficient protection system. Following the seminal discovery of Steinman and Cohen in 1974 describing a rare cell type capable of initiating antigen-specific responses in lymphnodes, Dendritic Cells (DC) have taken up the stage for several decades as professional Antigen Presenting Cells (APC). Although DC possess all attributes to prime naïve T lymphocytes, other immune cell subsets become crucial accessory cells during secondary and even primary activation. For instance, Monocytes (Mo) are rapidly recruited to inflammatory sites and have recently been recognized as capable of shaping T cell immunity, either directly through Ag presentation, or indirectly through the secretion of soluble factors. In addition, upon sensing of T cell-derived cytokines, Mo differentiate into functionally different APC types that further impact on the quality and persistence of memory T cell responses in peripheral tissues. Other innate immune cells, including Myeloid Derived Suppressor Cells, Granulocytes and iNKT lymphocytes, are known to modulate T cell activation by interacting with and modifying the function of professional APC. Notably, innate immune cell determinants also account for the tissue-specific regulation of T cell immunity. Hence, the newly discovered family of Innate Lymphoid Cells, has been recognized to shape CD4+ T cell responses at mucosal surfaces. Although the actions of innate immune cells fulfills the need of initiating and maintaining protective T cell responses, the excessive presence or activity of individual determinants may be detrimental to the host, because it could promote tissue destruction as in autoimmunity and allergy, or conversely, prevent the induction of immune responses against malignant tissues, and even modulate the response to therapeutic agents. Thus, understanding how defined innate immune cell subsets control T cell immunity is of fundamental relevance to understand human health, and of practical relevance for preventing and curing human diseases. In this research topic, we intend to provide an excellent platform for the collection of manuscripts addressing in depth how diverse innate immune cell subsets impact on T cell responses through molecularly defined pathways and evaluating the rational translation of basic research into clinical applications.

This book highlights recent research and advances in natural product chemistry written by promising young researchers in this field who have played a central role for recent innovative advancements. The book consists of seventeen chapters covering novel bioactive natural products, uncovering life phenomena with natural products, biosynthesis of natural products, total synthesis of complex natural products by innovative strategies, and drug discovery using natural products. Each chapter begins with a brief and easy-to-understand introduction, then presents the cutting-edge research in each individual specialty. This book is not only a practical and essential reference resource for natural product chemists, medicinal chemists, synthetic organic chemists, biochemists, pharmacologists, as well as the pharmaceutical and biotechnological industries, but is also a useful guide to understanding new and emerging trends in this field.

For four decades, physicians and other healthcare providers have trusted Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases to provide expert guidance on the diagnosis and treatment of these complex disorders. The 9th Edition continues the tradition of excellence with newly expanded chapters, increased global coverage, and regular updates to keep you at the forefront of this vitally important field. Meticulously updated by Drs. John E. Bennett, Raphael Dolin, and Martin J. Blaser, this comprehensive, two-volume masterwork puts the latest information on challenging infectious diseases at your fingertips. Provides more in-depth coverage of epidemiology, etiology, pathology, microbiology, immunology, and treatment of infectious agents than any other infectious disease resource. Features an increased focus on antibiotic stewardship; new antivirals for influenza, cytomegalovirus, hepatitis C, hepatitis B., and immunizations; and new recommendations for vaccination against infection with pneumococci, papillomaviruses, hepatitis A, and pertussis. Covers newly recognized enteroviruses causing paralysis (E-A71, E-D68); emerging viral infections such as Ebola, Zika, Marburg, SARS, and MERS; and important updates on prevention and treatment of C. difficile infection, including new tests that diagnose or falsely over-diagnose infectious diseases. Offers fully revised content on bacterial pathogenesis, antibiotic use and toxicity, the human microbiome and its effects on health and disease, immunological mechanisms and immunodeficiency, and probiotics and alternative approaches to treatment of infectious diseases. Discusses up-to-date topics such as use of the new PCR panels for diagnosis of meningitis, diarrhea and pneumonia; current management of infected orthopedic implant infections; newly recognized infections transmitted by black-legged ticks in the USA: Borrelia miyamotoi and Powassan virus; infectious complications of new drugs for cancer; new drugs for resistant bacteria and mycobacteria; new guidelines for diagnosis and therapy of HIV infections; and new vaccines against herpes zoster, influenza, meningococci. PPID continues its tradition of including leading experts from a truly global community, including authors from Australia, Canada and countries in Europe, Asia, and South America. Features more than 1,500 high-quality, full-color photographs—with hundreds new to this edition.