Journal article

TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection

Francesca Alfei, Kristiyan Kanev, Maike Hofmann, Ming Wu, Hazem E Ghoneim, Patrick Roelli, Daniel T Utzschneider, Madlaina von Hoesslin, Jolie G Cullen, Yiping Fan, Vasyl Eisenberg, Dirk Wohlleber, Katja Steiger, Doron Merkler, Mauro Delorenzi, Percy A Knolle, Cyrille J Cohen, Robert Thimme, Benjamin Youngblood, Dietmar Zehn

Nature | NATURE PUBLISHING GROUP | Published : 2019

Abstract

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential1-4. This process, known as T cell exhaustion or dysfunction1, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)5-8. The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T c..

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Grants

Awarded by Swiss National Science Foundation


Awarded by German Research Foundation


Awarded by German-Israeli Foundation for Scientific Research and Development (GIF) grant


Awarded by German Research Foundation grants


Awarded by NIH


Awarded by CRC


Funding Acknowledgements

We thank M. J. Bevan and M. Prlic for input, feedback and suggestions; T. Herbinger and B. Dotterbock; W. Schmid and C. Amette for technical assistance; and S. Schleicher and C. Lechner for animal husbandry. Work in the D.Z. laboratory was supported by a 'European Research Council starting grant' (ProtecTC) and subsequently a 'European Research Council consolidator grant' (ToCCaTa), grants from the Swiss National Science Foundation (CRSII3 160708, 310030E-164187, 51PHP0 157319 and PP00P3_144883), the Swiss Vaccine Research Institute (SVRI) and grants from the German Research Foundation (SFB1054). D.Z. and C. J. C. are supported by a German-Israeli Foundation for Scientific Research and Development (GIF) grant (I-1440-414.13/2017). K.S. is supported by German Research Foundation grants (SFB824 and SFB1335). R.T. and M.H. are funded by a German Research Foundation grant (TRR179-TP01). B.Y. is supported by the NIH (R01AI114442) and the American Lebanese Syrian Associated Charities (ALSAC). P.A.K. is supported by the Germany Center for Infection Research Munich site and the CRC TRR179.