Immunology

Immunology is now a major component of studies in human biology, with many diseases having immune system involvement. Because so many areas of study include aspects of immunological knowledge, how to teach and incorporate immunology must be evaluated and assessed at all levels of education including K-12, undergraduate, graduate, medical, and professional programs. Traditional teaching methods such as lecture have significant shortcomings which make them less appealing to students today who are more digitally inclined and demand more active and engaging learning environments. Herein, we describe and propose the use of the active learning model of Team-Based Learning (TBL) to incorporate immunology into medical and professional programs. TBL is defined as an evidence based collaborative learning strategy taught in a three-step cycle: pre-class preparation, in-class readiness assurance testing (RAT), and application-focused exercises. In TBL, students are assigned to 6–7 member teams. Students complete the in-class RAT individually followed by taking the RAT as a team (T-RAT). Following the RAT and T-RAT, the instructor can then provide immediate feedback on concepts that proved especially difficult. The remainder of class time is then spent with teams working case studies and applications relative to the instructional topic or disease. Teams decide the best outcome or answer for a given application and report their answers simultaneously in class, followed by a discussio

‘T cell exhaustion’ is a broad term that has been used to describe the response of T cells to chronic antigen stimulation, first in the setting of chronic viral infection but more recently in response to tumours. Understanding the features of and pathways to exhaustion has crucial implications for the success of checkpoint blockade and adoptive T cell transfer therapies. In this Viewpoint article, 18 experts in the field tell us what exhaustion means to them, ranging from complete lack of effector function to altered functionality to prevent immunopathology, with potential differences between cancer and chronic infection. Their responses highlight the dichotomy between terminally differentiated exhausted T cells that are TCF1– and the self-renewing TCF1+ population from which they derive. These TCF1+ cells are considered by some to have stem cell-like properties akin to memory T cell populations, but the developmental relationships are unclear at present. Recent studies have also highlighted an important role for the transcriptional regulator TOX in driving the epigenetic enforcement of exhaustion, but key questions remain about the potential to reverse the epigenetic programme of exhaustion and how this might affect the persistence of T cell populations. In this Viewpoint article, Nature Reviews Immunology invites 18 experts to discuss the nature of T cell exhaustion. How should T cell exhaustion be defined and what are the developmental relationships between exhausted T cell subsets? The contributors share their thoughts on key recent developments in the field. Christian U. Blank is a medical oncologist and principal investigator at the Netherlands Cancer Institute. He is Professor of Haematology/Oncology at the University of Regensburg, Germany, and received an MBA degree from the University of Warwick, UK. His research interests include neoadjuvant immunotherapies, targeted and biological response modifiers, and prognostic markers for cancer immunotherapies. W. Nicholas Haining is a physician–scientist and Vice-President for Discovery Oncology and Immunology at Merck Research Laboratories. His former academic laboratory at the Dana-Farber Cancer Institute and the Broad Institute focused on understanding the transcriptional control of T cell exhaustion and on identifying regulators of the immune response to cancer in tumour and immune cells. Werner Held’s laboratory has a long-standing interest in understanding the development, differentiation and function of natural killer cells and CD8+ T cells. Current work focuses on CD8+ T cell differentiation in response to acute and chronic infections as well as cancer. Patrick G. Hogan’s research centres on mechanisms and regulation of cellular calcium signalling, the biology of the nuclear factor of activated T cells (NFAT) family of transcription factors and the transcriptional control of immune cell development and function. Axel Kallies is a professor at the University of Melbourne, Australia. His laboratory studies the molecular control of CD8+ cytotoxic T cell and regulatory T cell differentiation with a focus on populations residing in non-lymphoid tissue, including healthy tissues and tumours. The Kallies laboratory has developed and applied genetic and molecular approaches to this field, including novel gene reporters, metabolic techniques, transcriptional profiling, chromatin immunoprecipitation and accessible chromatin sequencing. Enrico Lugli’s laboratory is focused on understanding the biological mechanisms at the basis of memory T cell responses and homeostasis in humans and how this information can be exploited to favour antitumour immune responses in patients with cancer. The group is specialized in single-cell technologies, in particular high-dimensional flow cytometry. Rachel C. Lynn is an associate director of research at Lyell Immunopharma. She received her PhD degree from the the University of Pennsylvania, where she developed multiple preclinical chimeric antigen receptor (CAR) T cell therapy platforms. During her postdoctoral work with Crystal Mackall at Stanford University, she developed models to interrogate and strategies to mitigate CAR T cell exhaustion. At Lyell Immunopharma, her research group will continue to investigate optimal strategies for adoptive T cell therapy in cancer. Mary Philip is an assistant professor in the Department of Medicine, Division of Hematology and Oncology and Department of Pathology, Microbiology, and Immunology at Vanderbilt University Medical Center. She did her haematology and oncology fellowship training at the Fred Hutchinson Cancer Research Center and the University of Washington and then joined Andrea Schietinger’s group at Memorial Sloan Kettering Cancer Center investigating the epigenetic and transcriptional regulation of T cell dysfunction and reprogrammability in cancer. She is a physician–scientist with clinical expertise in haematological cancers, and her research group at Vanderbilt University Medical Center is developing innovative models to dissect the regulation of T cell dysfunction in cancer and T cell lymphomas. Anjana Rao’s laboratory studies transcriptional regulation in several cell types, including CD4+ and CD8+ T cells. One current focus is elucidation of the transcriptional and epigenetic regulatory mechanisms operating in T cells and other immune cells within the tumour microenvironment. Nicholas P. Restifo was trained at Memorial Sloan Kettering Cancer Center and was a principal investigator at the National Cancer Institute. His work has focused on the use of adoptively transferred T cells in immunotherapy for cancer for the past 31 years. He recently joined Lyell Immunopharma. Andrea Schietinger is an assistant member in the Immunology Program at Memorial Sloan Kettering Cancer Center. During her PhD studies with Hans Schreiber at the University of Chicago, she studied how aberrant glycosylation of wild-type proteins in cancer cells creates tumour-specific neoantigens. As a postdoctoral fellow in Philip Greenberg’s laboratory at the University of Washington in Seattle, she defined the transcriptional programmes associated with T cell self-tolerance and tumour-specific T cell dysfunction. Her laboratory at Memorial Sloan Kettering Cancer Center studies the regulatory molecular and epigenetic mechanisms underlying T cell differentiation and dysfunction in the context of self-tolerance, autoimmunity and tumours. Ton N. Schumacher is a principal investigator at the Netherlands Cancer Institute and Professor of Immunotechnology at Leiden University. His research focuses on the dissection of tumour-specific T cell responses in human cancer. In addition to his academic role, he is the founder of four biotech companies and a venture partner at Third Rock Ventures. Pamela L. Schwartzberg is a senior investigator at the National Institute of Allergy and Infectious Diseases. She completed her MD and PhD degrees at Columbia University and her postdoctoral studies at the National Cancer Institute. Her laboratory studies signalling pathways in T cells using genetic, cellular, biochemical and genomic approaches to understand how these affect responses to infection and immunization with a focus on molecules and pathways affected by primary immunodeficiencies. Arlene H. Sharpe is Chair of the Department of Immunology at Harvard Medical School. Her laboratory focuses on understanding the diverse roles of costimulatory and coinhibitory signals in infection, autoimmunity and cancer. Daniel E. Speiser’s team has investigated and treated cancer patients with immunotherapy for the past 30 years. The demonstration and mechanistic elucidation of graft-versus-leukaemia effects and autologous T cell reactivity have helped to pave the way for remarkable therapy innovations in oncology. E. John Wherry is the Barbara and Richard Schiffrin President’s Distinguished Professor, Chair of the Department of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine and Director of the Penn Institute for Immunology. His research has focused on T cell exhaustion in chronic viral infections and cancer. His work has defined the developmental biology and molecular regulation of T cell exhaustion and used this information to inform immunotherapy for human cancer. Benjamin A. Youngblood is an associate member in the Department of Immunology at St Jude Children’s Research Hospital. His postdoctoral training in Rafi Ahmed’s laboratory focused on the epigenetic regulation of memory CD8+ T cell differentiation. In 2014, he joined the faculty at St Jude Children’s Research Hospital and has developed a research programme studying epigenetic mechanisms that regulate the development of functional and non-functional CD8+ T cells during viral infection, cancer and autoimmunity. Dietmar Zehn is a full professor and Chair of the Division of Animal Physiology and Immunology of the Technical University of Munich. His research focuses on understanding the molecular and cellular mechanisms that control the differentiation of T cells in acute and chronic infection, with specific interests in T cell exhaustion and T cell receptor signal strength.

Exciting new discoveries have transformed the view of the lysosome from a static organelle dedicated to the disposal and recycling of cellular waste to a highly dynamic structure that mediates the adaptation of cell metabolism to environmental cues. Lysosome-mediated signalling pathways and transcription programmes are able to sense the status of cellular metabolism and control the switch between anabolism and catabolism by regulating lysosomal biogenesis and autophagy. The lysosome also extensively communicates with other cellular structures by exchanging content and information and by establishing membrane contact sites. It is now clear that lysosome positioning is a dynamically regulated process and a crucial determinant of lysosomal function. Finally, growing evidence indicates that the role of lysosomal dysfunction in human diseases goes beyond rare inherited diseases, such as lysosomal storage disorders, to include common neurodegenerative and metabolic diseases, as well as cancer. Together, these discoveries highlight the lysosome as a regulatory hub for cellular and organismal homeostasis, and an attractive therapeutic target for a broad variety of disease conditions. Lysosomes are mainly associated with cellular waste disposal. But it has recently been discovered that by integrating various environmental cues, they have a broader role as regulatory hubs for cellular and organismal homeostasis. The modulation of lysosome function could thus be a promising therapeutic strategy for the treatment of cancer as well as metabolic and neurodegenerative disorders.

Multiple type I interferons and interferon-γ (IFN-γ) are expressed under physiological conditions and are increased by stress and infections, and in autoinflammatory and autoimmune diseases. Interferons activate the Jak–STAT signaling pathway and induce overlapping patterns of expression, called ‘interferon signatures’, of canonical interferon-stimulated genes (ISGs) encoding molecules important for antiviral responses, antigen presentation, autoimmunity and inflammation. It has now become clear that interferons also induce an ‘interferon epigenomic signature’ by activating latent enhancers and ‘bookmarking’ chromatin, thus reprogramming cell responses to environmental cues. The interferon epigenomic signature affects ISGs and other gene sets, including canonical targets of the transcription factor NF-κB that encode inflammatory molecules, and is involved in the priming of immune cells, tolerance and the training of innate immune memory. Here we review the mechanisms through which interferon signatures and interferon epigenomic signatures are generated, as well as the expression and functional consequences of these signatures in homeostasis and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis. Ivashkiv and colleagues review the mechanisms by which IFN signatures and IFN epigenomic signatures are generated, as well as the functional consequences of these signatures in homeostasis and autoimmune diseases.

Treg play a central role in maintenance of self tolerance and homeostasis through suppression of self-reactive T cell populations. In addition to that role, Treg also survey cancers and suppress anti-tumor immune responses. Thus, understanding the unique attributes of Treg-tumor interactions may permit control of this pathologic suppression without interfering with homeostatic self-tolerance. This review will define the unique role of Treg in cancer growth, and the ways by which Treg inhibit a robust anti-tumor immune response. There will be specific focus placed on Treg homing to the tumor microenvironment (TME), TME formation of induced Treg (iTreg), mechanisms of suppression that underpin cancer immune escape, and trophic nonimmunologic effects of Treg on tumor cells.

Mycobacterium tuberculosis, the leading cause of death due to infection, has a dynamic and immunomodulatory cell envelope. The cell envelope structurally and functionally varies across the length of the cell and during the infection process. This variability allows the bacterium to manipulate the human immune system, tolerate antibiotic treatment and adapt to the variable host environment. Much of what we know about the mycobacterial cell envelope has been gleaned from model actinobacterial species, or model conditions such as growth in vitro, in macrophages and in the mouse. In this Review, we combine data from different experimental systems to build a model of the dynamics of the mycobacterial cell envelope across space and time. We describe the regulatory pathways that control metabolism of the cell wall and surface lipids in M. tuberculosis during growth and stasis, and speculate about how this regulation might affect antibiotic susceptibility and interactions with the immune system. Mycobacterium tuberculosis has a distinctive cell envelope that contributes to its resistance against the human immune system and antibiotic therapy. In this Review, Dulberger, Rubin and Boutte discuss mycobacterial cell envelope dynamics and their relevance for infection and drug treatment.

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The tumour microenvironment (TME) highly influences the growth and spread of tumours, thus impacting the patient’s clinical outcome. In this context, the complement system plays a major and complex role. It may either act to kill antibody-coated tumour cells, support local chronic inflammation or hamper antitumour T cell responses favouring tumour progression. Recent studies demonstrate that these opposing effects are dependent upon the sites of complement activation, the composition of the TME and the tumour cell sensitivity to complement attack. In this Review, we present the evidence that has so far accrued showing a role for complement activation and its effects on cancer control and clinical outcome under different TME contexts. We also include a new analysis of the publicly available transcriptomic data to provide an overview of the prognostic value of complement gene expression in 30 cancer types. We argue that the interplay of complement components within each cancer type is unique, governed by the properties of the tumour cells and the TME. This concept is of critical importance for the design of efficient therapeutic strategies aimed at targeting complement components and their signalling. This Review discusses the complex and context-dependent role of the complement system in cancer, highlighting the opposing effects of complement activation in both promoting and restraining tumour progression. A novel analysis of publicly available transcriptomic data to provide an overview of the prognostic value of complement gene expression in cancer is also included.