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Review
. 2019 Nov;19(11):665-674.
doi: 10.1038/s41577-019-0221-9. Epub 2019 Sep 30.

Defining 'T cell exhaustion'

Christian U Blank  1 , W Nicholas Haining  2 , Werner Held  3 , Patrick G Hogan  4   5 , Axel Kallies  6 , Enrico Lugli  7 , Rachel C Lynn  8 , Mary Philip  9 , Anjana Rao  10   11   12 , Nicholas P Restifo  13 , Andrea Schietinger  14 , Ton N Schumacher  15 , Pamela L Schwartzberg  16 , Arlene H Sharpe  17 , Daniel E Speiser  18 , E John Wherry  19 , Benjamin A Youngblood  20 , Dietmar Zehn  21
Affiliations
Review

Defining 'T cell exhaustion'

Christian U Blank et al. Nat Rev Immunol. 2019 Nov.

Abstract

'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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Conflict of interest statement

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.

Figures

Fig. 1 |
Fig. 1 |. The knowns and unknowns of T cell exhaustion.
Potential developmental relationships between and features of exhausted T cell subsets compared with effector and memory T cell suswbsets during chronic versus acute antigen stimulation.
See this image and copyright information in PMC

References

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    1. Wherry EJ T cell exhaustion. Nat. Immunol 12, 492–499 (2011). - PubMed
    1. McLane LM, Abdel-Hakeem MS & Wherry EJ CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol 37, 457–495 (2019). - PubMed
    1. Martinez GJ et al. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity 42, 265–278 (2015). - PMC - PubMed

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