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OPINION

Precursor exhausted T cells: key to successful immunotherapy?

Nature Reviews Immunology volume 20, pages 128–136 (2020)Cite this article

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Abstract

Cytotoxic T cell immunity in response to chronic infections and tumours is maintained by a specialized population of CD8+ T cells that exhibit hallmarks of both exhausted and memory cells and give rise to terminally differentiated exhausted effector cells that contribute to viral or tumour control. Importantly, recent work suggests these cells, which we refer to as ‘precursor exhausted’ T (TPEX) cells, are responsible for the proliferative burst that generates effector T cells in response to immune checkpoint blockade targeting programmed cell death 1 (PD1), and increased TPEX cell frequencies have recently been linked to increased patient survival. We believe the recent discovery of TPEX cells not only represents a paradigm shift in our understanding of the mechanisms that maintain CD8+ T cell responses in chronic infections and tumours but also opens up unexpected avenues for the development of new and innovative therapeutic approaches. In this Opinion article, we discuss the differentiation and function of TPEX cells and suggest that targeting these cells may be key for successful immunotherapy.

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Fig. 1: Transcriptional regulation of TPEX and TEX cells.
Fig. 2: TPEX cells maintain T cell responses in chronic infections and respond to checkpoint blockade.

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Acknowledgements

The authors thank the members of the Kallies and Zehn laboratories, in particular S. Gabriel, A. Vasanthakumar and P. Gubser for discussions. A.K. is a fellow of the Australian National Health and Medical Research Council. D.T.U. is a special fellow of The Leukemia and Lymphoma Society.

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Nature Reviews Immunology thanks N. Restifo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Microbiology & Immunology Melbourne, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia

    Axel Kallies & Daniel T. Utzschneider

  2. Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany

    Dietmar Zehn

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  1. Axel Kallies
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Contributions

D.T.U. and A.K. researched data and wrote the article, and D.Z. contributed to scientific discussion.

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Correspondence to Axel Kallies or Daniel T. Utzschneider.

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The Nobel Prize in Physiology or Medicine 2018: https://www.nobelprize.org/prizes/medicine/2018/summary/

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Kallies, A., Zehn, D. & Utzschneider, D.T. Precursor exhausted T cells: key to successful immunotherapy?. Nat Rev Immunol 20, 128–136 (2020). https://doi.org/10.1038/s41577-019-0223-7

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