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T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Nature Reviews Immunology volume 14, pages 768–774 (2014)Cite this article

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Abstract

Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors.

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Figure 1: Assessing T cell differentiation in acute and chronic infections.
Figure 2: Proposed model for T cell responses in chronic infection.

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Acknowledgements

D.E.S., C.M., P.R. and D.Z. are supported by a Swiss National Science Sinergia grant (FNS CRSII3_141879).

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Authors and Affiliations

  1. Department of Oncology, Ludwig Cancer Research Center, University of Lausanne, Lausanne, 1011, Switzerland

    Daniel E. Speiser

  2. and the Division of Immunology and Allergy, Department of Medicine, Swiss Vaccine Research Institute, Centre des laboratoires d'Epalinges, 1066 Epalinges, Switzerland, Lausanne University Hospital, 1011 Lausanne, Switzerland.,

    Daniel T. Utzschneider, Susanne G. Oberle & Dietmar Zehn

  3. Institute for Experimental Immunology, University of Zürich, Zürich, CH-8057, Switzerland

    Christian Münz

  4. Department of Oncology, Ludwig Cancer Research Center, University of Lausanne, Lausanne, 1011, Switzerland

    Pedro Romero

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Speiser, D., Utzschneider, D., Oberle, S. et al. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?. Nat Rev Immunol 14, 768–774 (2014). https://doi.org/10.1038/nri3740

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