Wistar scientists find key to keeping killer T cells in prime shape for fighting infection, cancer

December 01, 2008

Like tuning a violin to produce strong, elegant notes, researchers at The Wistar Institute have found multiple receptors on the outside of the body's killer immune system cells which they believe can be selectively targeted to keep the cells in superb infection- and disease-fighting condition.

In a study published online November 30 in Nature Immunology, the researchers describe their discovery of seven different receptors on T cells that can tamp down immune responses during a prolonged battle with an infectious pathogen or against developing cancer.

Chronic over-stimulation of the immune system can lead to poor control of infections and cancer, so the results explain why it is that these key immune cells gradually become "exhausted" and ineffective over time, says the study's lead author, E. John Wherry, Ph.D., an assistant professor in Wistar's Immunology Program.

Wherry had recently been involved in discovering a single receptor involved in turning off T cells but this new study shows that at least six more receptors can also restrain or negatively regulate immune responses. According to Wherry, a key finding is that these new receptors likely control different aspects of T cell responses, such as division or expansion, controlling viral replication, and local killing of infected cells versus secretion of long-range active antiviral proteins.

"This amount of control over T cells' response is remarkable. It suggests that layers of negative regulation exist on exhausted T cells from co-expression of multiple inhibitory receptors," he says. "My bet is that these receptors inhibit different aspects of the T cells' response, but that the net result of their activation is to turn specific T cell populations off.

"We are starting to see a picture emerging of a really tuneable array of inhibitory receptors expressed on T cells," Wherry says. "That suggests it may be possible to not only dramatically enhance antiviral or antitumor T cell responses, but also to fine tune which response you want to enhance in order to reverse T cell exhaustion and continue fighting an infection or disease.

"This presents us with a great clinical opportunity," Wherry says. "T cells have a lot of weapons at their disposal to control viral infection and most of them are disarmed when these cells become exhausted. It may be possible to selectively rearm T cells while generally reinvigorating them."

The researchers made their discoveries in a mouse model of chronic infection with lymphocytic choriomeningitis virus. They had earlier found that a receptor known as programmed death-1 (PD-1) was highly expressed by exhausted T cells from chronically infected mice but not from mice that had cleared the infection. In a study published September 15 in the Proceedings of the National Academy of Sciences (PNAS), the researchers extended previous studies on the role of the PD-1 pathway in regulating T cell exhaustion. In these studies, blocking PD-1 increased T cell response, but not completely, so the researchers suspected other negative regulatory pathways were activated as well.

In the newest report in Nature Immunology, Wherry and colleagues compared the global patterns of gene expression for exhausted killer T cells compared to other types of T cells (na�-ve, effector and memory). A "nearest neighbor" analysis to PD-1 revealed up-regulation of six other inhibitory receptor genes. They are LAG3, 2B4, CD160, CTLA-4, PIR-B and GP49. While the function of many of these receptors has been characterized, they had not been known to play a role in chronic viral infection. LAG-3, for example, is associated with an antitumor response. These observations may explain why PD-1 blockade did not completely restore T cell responses in previous work.

The investigators discovered that the severity of chronic infection correlated with the number and intensity of inhibitory receptor expression, suggesting a cumulative impact of inhibitory receptor expression. They also found that blocking both PD-1 and LAG-3 together led to substantially greater improvement in T cell responses and viral control compared to either blockade alone.

"The goal now is to understand the pathways the receptors control, and then to learn how to fine tune reversal of exhaustion by targeting pathways that selectively control the desired type of T cell response," Wherry says.

The Wistar Institute

The Immune System
by Peter Parham (Author)

The Immune System, Third Edition emphasizes the human immune system and synthesizes immunological concepts into a comprehensible, up-to-date, and reader-friendly account of how the immune system works. Written for undergraduate, medical, veterinary, dental, and pharmacy students in immunology courses, it makes generous use of medical examples to illustrate points. The Third Edition has been extensively revised and updated and includes two new chapters on innate and adaptive immunity, which explore the physical, cellular, and molecular principles underlying these responses to infection. It also features enhanced coverage of aspects of innate immunity such as the complement system, Toll-like receptors, defensins, and C-reactive protein; the role of dendritic cells in...

In Defense of Self: How the Immune System Really Works
by William R. Clark (Author)

We live in a sea of seething microbial predators, an infinity of invisible and invasive microorganisms capable of setting up shop inside us and sending us to an early grave. The only thing keeping them out? The immune system.

William Clark's In Defense of Self offers a refreshingly accessible tour of the immune system, putting in layman's terms essential information that has been for too long the exclusive province of trained specialists. Clark explains how the immune system works by using powerful genetic, chemical, and cellular weapons to protect us from the vast majority of disease-causing microbes-bacteria, viruses, molds, and parasites. Only those microbes our bodies need to help us digest food and process vitamins are admitted. But this same system can endanger us by...

How the Immune System Works (Blackwell's How It Works)
by Lauren M. Sompayrac (Author)

Understanding the immune system is crucial for both medical and bioscience students, with new research revealing yet more secrets year on year. Many books offer in-depth introductions to the subject, but How the Immune System Works remains uniquely popular for its personable and practical overview of the nuts and bolts of the immune system.
This third edition provides a perfect introduction to the essential principles of the immune system, covered in humorous but highly informative 'lectures' accompanied by clear and accessible illustrations. It is perfect for exam preparation or as an enjoyable overview of a difficult subject. Both students and instructors will welcome the clarity and authority that Lauren Sompayrac brings to this timely revision.

How the Immune System Works, Includes FREE Desktop Edition (BLACKWELL'S HOW IT WORKS SERIES)
by Lauren M. Sompayrac (Author)

How the Immune System Works is not a comprehensive textbook. It’s the book thousands of students have used to help them understand what’s in their big, thick, immunology texts. In this book, Dr. Sompayrac cuts through the jargon and details to reveal, in simple language, the essence of this complex subject.

Fifteen easy to follow lectures, featuring the uniquely popular humorous style and engaging analogies developed by Dr Sompayrac, provide an introduction to the ‘bigger picture’, followed by practical discussion on how each of the components interacts with one another. Now featuring full-color diagrams, this book has been rigorously updated for its fourth edition to reflect today’s immunology teaching and includes updated discussion of B and T cell memory, T cell...

90 Day Immune System Revised: This vital life-saving information will help you: Protect your body from diseases and early aging Maximize your ... and surveys Boost your vitality and b
by Janet Maccaro (Author)

GIVE YOURSELF 90 DAYS TO... Build and strengthen your immune system. Bring your body's system into proper balance Experience disease-free living. No matter what your health has been in the past, there is something you can do right now to give your entire body a complete makeover! Dr. Janet explains how you can improve the quality of your life with: Imagine what your life could be like with a complete immune system makeover! You best days of health are ahead of you. What are you waiting for?

The Immune System
by Peter Parham (Author)

The Immune System, Second Edition has been designed for use in immunology courses for undergraduate, medical, dental, and pharmacy students. This class-tested and successful textbook synthesizes the established facts of immunology into a comprehensible, coherent, and up-to-date account of how the immune system works, rather than presenting immunology as a chronology of experiments and discoveries. Emphasizing the human immune system the text has been designed to break down the barriers which often divide basic and clinical immunology. The reader-friendly text, section and chapter summaries, and full-color illustrations make the book accessible and easily understandable to students. The Immune System is adapted from Immunobiology by Janeway, Travers & Walport.

Digestive Wellness: Strengthen the Immune System and Prevent Disease Through Healthy Digestion, Fourth Edition
by Elizabeth Lipski (Author)

The definitive guide to healthy digestion! Digestive Wellness explains how your digestive system works and what to do when it doesn’t. You’ll find practical solutions to all the common gastrointestinal disorders (and many other conditions) and expert guidance on the newest advances in testing and diagnosis, nutrition, and natural therapies. Plus, you’ll learn how faulty digestion can affect the human body systemically, from migraines and skin issues to fibromyalgia and chronic fatigue syndrome. “Dr. Lipski offers a practical toolkit to support each of us—clinicians and patients—to return to wellness by bringing our gastrointestinal system back into balance and harmony. I believe that you will deeply benefit from joining Dr. Lipski on this journey toward digestive...

Basic Immunology Updated Edition: Functions and Disorders of the Immune System With STUDENT CONSULT Online Access, 3e (Basic Immunology: Functions and Disorders of the Immune System)
by Abul K. Abbas MBBS (Author), Andrew H. Lichtman MD PhD (Author)

This updated 3rd edition of Basic Immunology provides a readable and concise introduction to the workings of the human immune system, with emphasis on clinical relevance. The format makes learning easy with short, easy-to-read chapters, color tables, key point summaries, and review questions in every chapter. You'll get the latest coverage on regulatory T cells, biology of the Th17 subset of CD4+ T cells, and more. The full-color artwork, comprehensive glossary, and clinical cases are just some of the features that reinforce and test your understanding of how the immune system functions. Student Consult online access lets you search the full text online and pursue further study through integration links. Covers the most up-to-date immunology information including regulatory T cells, and...

The Immune System Cure: Optimize Your Immune System in 30 Days-The Natural Way!
by Lorna Vanderheaghe (Author)

What causes one person to catch a cold or flu and another to avoid it? Why do serious outbreaks of infectious diseases leave some individuals untouched? What allows someone to be incapacitated by allergies? The answer lies within nature itself-our immune system. The Immune System Cure provides simple techniques for supercharging your immune system to resist and prevent disease. Through diet, exercise, stress reduction and nutritional supplements, including plant sterols and sterolins, you can harness the power of your immune system in just 30 days and help it combat: Antibiotic-resistant bacteria Fibromyalgia Allergies Hepatitis C Tuberculosis Cancer Rheumatoid arthritis and other autoimmune diseases Chronic fatigue syndrome and more Now you can maintain a healthy...

Super Immunity: The Essential Nutrition Guide for Boosting Your Body's Defenses to Live Longer, Stronger, and Disease Free
by Joel Fuhrman (Author)

Why do some of us get sick with greater frequency than others?
What makes us more susceptible to illness?
Are we doomed to get sick when our coworkers and family members do?
Is there a secret to staying healthy? Joel Fuhrman, M.D., a leading expert and board-certified medical specialist in prevention and reversing disease, offers a comprehensive guide to superior health. Based on the latest scientific research, Super Immunity shows us how we can become almost totally resistant to colds, influenza, and other infections. The evidence is overwhelming: we can supercharge our immune system to protect our bodies against disease—everything from the common cold to cancer. Nutritional science has made phenomenal strides and discoveries in recent years, and when this new...