Defining 'T cell exhaustion'.

Blank CU; Haining WN; Held W; Hogan PG; Kallies A; Lugli E; Lynn RC; Philip M; Rao A; Restifo NP; Schietinger A; Schumacher TN; Schwartzberg PL; Sharpe AH; Speiser DE; Wherry EJ; Youngblood BA; Zehn D

doi:10.1038/s41577-019-0221-9

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Journal article

Defining 'T cell exhaustion'.

Blank CU Netherlands Cancer Institute, Amsterdam, Netherlands. c.blank@nki.nl.
Haining WN Discovery Oncology, Merck Research Laboratories, Boston, MA, USA. nick.haining@merck.com.
Held W Department of Oncology, University of Lausanne, Lausanne, Switzerland. Werner.held@unil.ch.
Hogan PG La Jolla Institute for Immunology, La Jolla, CA, USA. phogan@lji.org.
Kallies A Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. axel.kallies@unimelb.edu.au.
Lugli E Laboratory of Translational Immunology and Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center, Rozzano, Italy. enrico.lugli@humanitasresearch.it.
Lynn RC Lyell Immunopharma, South San Francisco, CA, USA. rlynn@lyell.com.
Philip M Vanderbilt University Medical Center, Nashville, TN, USA. mary.philip@vumc.org.
Rao A La Jolla Institute for Immunology, La Jolla, CA, USA. arao@lji.org.
Restifo NP Lyell Immunopharma, South San Francisco, CA, USA. nrestifo@lyell.com.
Schietinger A Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. schietia@mskcc.org.
Schumacher TN Netherlands Cancer Institute, Amsterdam, Netherlands. t.schumacher@nki.nl.
Schwartzberg PL National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. pams@nih.gov.
Sharpe AH Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. arlene_sharpe@hms.harvard.edu.
Speiser DE Department of Oncology, University of Lausanne, Lausanne, Switzerland. daniel.speiser@unil.ch.
Wherry EJ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.
Youngblood BA Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. benjamin.youngblood@stjude.org.
Zehn D Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany. dietmar.zehn@tum.de.

2019-10-02

Published in:

Nature reviews. Immunology. - 2019

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English '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.

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