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Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

Tonnerre P et al. (BioRxiv) DOI: 10.1101/2021.04.03.437705

Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory


  • T cell Exhaustion

  • Chronic antigen stimulation

  • T cell Recovery

Main Findings

T cell exhaustion is a common phenotype found in tumors which can be partially responsible for the absence of a successful anti-tumor immune response. Understanding the factors which lead to T cell exhaustion, and what can be done to rescue T cells from an exhausted state, could contribute to the efficacy of cancer immunotherapies.

Tonnerre and colleagues examine the exhausted T cell state in chronic human hepatitis C virus (HCV), a unique model in humans which allows for comparison of chronically-stimulated T-cells, chronically-stimulated T cells which have stimulation removed, and successful/healthy T cells within the same antiviral response, limiting a number of confounding variables present in other model systems. The authors perform a wide array of analyses on these populations, including flow cytometry analysis of 37 surface markers, cytokines, and transcription factors, functional assessment of the cytotoxic potential of these cells following ex-vivo peptide stimulation, and RNA sequencing across a variety of timepoints. Analysis of CD8+ T cells chronically stimulated with their cognate antigen reveals an exhausted phenotype characterized by increased PD-1 and Eomes expression, and decreased CD127 expression. These exhausted cells shift towards a more memory-like phenotype following removal of the cognate antigen through viral cure. This shift to a memory-like phenotype does not appear to improve the functional abilities of these exhausted T cells, and key differences remain in expression of transcription factors associated with maintaining the exhausted T cell lineage, including TOX, between memory-like T cells that were previously exhausted and true anti-HCV memory cells. Overall this pre-print demonstrates that removal of the cognate antigen of T cells early in the response allows for development of a functional memory response, while chronic stimulation leads to an exhausted phenotype that cannot be functionally rescued by removal of the cognate antigen due to pervasive transcriptional ‘scars’, but phenotypically moves towards a memory-like phenotype following viral cure.


The core limitation of this pre-print is the potential lack of applicability to other model systems, like the anti-tumor T cell response.


Detailed profiling of exhausted T cells over time, and under different conditions, is rare due to difficulty collecting a large enough number of exhausted T cells. This pre-print collected a large enough number of HCV-specific CD8+ T cells to perform a good depth of profiling and functional assays in humans, over a variety of time points and conditions.

Detailed phenotypic analysis, functional assays, and RNAseq on chronically-stimulated exhausted CD8+ T cells, exhausted T cells following removal of the cognate antigen, and non-chronically stimulated T cells within the same individuals, as well as memory T cells against the same pathogen, provides a repository of data which can be used as a reference for future studies to support results found in other model systems.


Reviewed by Ashley Reid as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow her on Twitter

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