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Defining ‘T cell exhaustion’


‘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.

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.

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.

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Fig. 1: The knowns and unknowns of T cell exhaustion.


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P.G.H. and A.R. are funded by National Institutes of Health grants AI109842, AI040127 and AI084167, and U01 DE028227. A.K. is supported by a fellowship by the National Health and Medical Research Council of Australia. E.L. is supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG20607).

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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Christian U. Blank, W. Nicholas Haining, Werner Held, Patrick G. Hogan, Axel Kallies, Enrico Lugli, Rachel C. Lynn, Mary Philip, Anjana Rao, Nicholas P. Restifo, Andrea Schietinger, Ton N. Schumacher, Pamela L. Schwartzberg, Arlene H. Sharpe, Daniel E. Speiser, E. John Wherry, Benjamin A. Youngblood or Dietmar Zehn.

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Competing interests

W.N.H. is an employee of Merck & Co. and a founder of Arsenal Biosciences. The La Jolla Institute for Immunology (LJI) has received a research grant from Lyell lmmunopharma to support aspects of the work of P.G.H. on transcriptional mechanisms in CD8+ T cells. E.L. receives preclinical research funding from Bristol-Myers Squibb. LJI is the recipient of a research grant from Lyell lmmunopharma, which supports studies in the laboratory of A.R. using mouse models to elucidate the transcriptional and epigenetic programmes operating in CD8+ tumour-infiltrating T cells. LJI has a pending patent, PCT/US201B/062354, covering the use and production of engineered immune cells to disrupt NFAT–AP-1 pathway transcription factors, including NR4A1/2/3, TOX and TOX2, with A.R. listed as one of the inventors. LJI is the recipient of a research grant from the Takeda-Sanford Innovation Alliance for research in the laboratory of A.R. related to NR4A in human CD8+ T cells. N.P.R. and R.C.L. are employees of Lyell Immunopharma. A.H.S. has patents on the PD1 pathway licenced by Roche/Genentech and Novartis, consults for Novartis, is on the scientific advisory boards for Surface Oncology, Sqz Biotech, Elstar Therapeutics, Elpiscience, Selecta and Monopteros, and has research funding from Novartis, Roche, Ipsen, UCB, Quark Ventures and Merck. E.J.W. is a member of the Parker Institute for Cancer lmmunotherapy, which supported the present study. E.J.W. has consulting agreements with and/or is on the scientific advisory board for Merck, Roche, Pieris, Elstar and Surface Oncology. E.J.W. has a patent licensing agreement on the PD1 pathway with Roche/Genentech. E.J.W. is a founder of Arsenal Biosciences. B.A.Y. has patents associated with epigenetic programming of T cells. He has received honoraria for speaking at companies (less than US$5,000). The other authors declare no competing interests.

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Blank, C.U., Haining, W.N., Held, W. et al. Defining ‘T cell exhaustion’. Nat Rev Immunol 19, 665–674 (2019).

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