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Nat Rev Immunol. 2014 Nov;14(11):768-74. doi: 10.1038/nri3740. Epub 2014 Sep 26.

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

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Ludwig Cancer Research Center, Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland.
Swiss Vaccine Research Institute, Centre des laboratoires d'Epalinges, 1066 Epalinges, Switzerland, and the Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland.
Institute for Experimental Immunology, University of Zürich, CH-8057 Zürich, Switzerland.


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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