Defining ‘T cell exhaustion’

Abstract

The contributors 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.

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

“…Studies using models of chronic viral infections show that T-cell exhaustion helps to balance the immune response to infection and immunopathology to the host. 237 Emerging studies suggest that mTOR In addition to exhaustion driven by repeated antigen stimulation, T cells may also become metabolically exhausted, in which nutrient insufficiency or other metabolic stressors program cells to adopt a dysfunctional state irrespective of their antigen specificity.…”

Why isListeria monocytogenessuch a potent inducer of CD8+ T‐cells?

“…The relevance of chronic versus acute infection is also an important area to consider, as chronic infections tend to induce T‐cell exhaustion (Blank et al, ; Wherry & Kurachi, ). We suggest that the acute nature of L. monocytogenes infection is an additional feature responsible for inducing a favourable environment for the induction of CMI because it does not lead to T‐cell exhaustion.…”

Projecting single-cell transcriptomics data onto a reference T cell atlas to interpret immune responses

“…While the presence of tumor-infiltrating T lymphocytes (TILs) in cancer lesions has been broadly associated with improved prognosis and response to immune checkpoint blockade 5,6 , scRNA-seq has uncovered a great diversity within TILs, revealing that distinct TIL states contribute differently to tumor control and response to immunotherapies [7][8][9] . Crucially, antigen persistence in cancer and chronic infections profoundly alters CD8 T cell differentiation and function, leading antigen-specific cells into a collection of states referred to as "exhaustion" 10 . Recent data has shown that exhausted CD8 T cells are phenotypically and functionally heterogeneous [11][12][13][14][15][16][17] .…”