Journal article

Early precursor T cells establish and propagate T cell exhaustion in chronic infection

Daniel T Utzschneider, Sarah S Gabriel, David Chisanga, Renee Gloury, Patrick M Gubser, Ajithkumar Vasanthakumar, Wei Shi, Axel Kallies

NATURE IMMUNOLOGY | NATURE PORTFOLIO | Published : 2020

Abstract

CD8+ T cells responding to chronic infections or tumors acquire an 'exhausted' state associated with elevated expression of inhibitory receptors, including PD-1, and impaired cytokine production. Exhausted T cells are continuously replenished by T cells with precursor characteristics that self-renew and depend on the transcription factor TCF1; however, their developmental requirements are poorly understood. In the present study, we demonstrate that high antigen load promoted the differentiation of precursor T cells, which acquired hallmarks of exhaustion within days of infection, whereas early effector cells retained polyfunctional features. Early precursor T cells showed epigenetic imprinti..

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Grants

Awarded by National Health and Medical Research Council


Awarded by Swiss National Science Foundation


Awarded by Leukemia and Lymphoma Society


Funding Acknowledgements

We thank T. Mason for technical support and T. Gebhardt, S. Nutt and members of the Kallies lab for discussions. This work was funded by the National Health and Medical Research Council (project grant no. 1085151 and Senior Research Fellowship no. 1139607 to A.K.), the Swiss National Science Foundation (fellowship nos. P300PA_177907 to D.T.U., P400PM_180807 to S.S.G. and P300PB_177934 to P.M.G.) and the Novartis Foundation for Medical-Biological Research (fellowship to S.S.G.). D.T.U. is a Special Fellow of the Leukemia and Lymphoma Society (fellowship no. 338719). W.S.is supported by a WEHI Centenary Fellowship funded by a donation from CSL Ltd. We acknowledge the Melbourne Cytometry Platform for provision of flow cytometry services.