T cell exhaustion

  title={T cell exhaustion},
  author={E. John Wherry},
  journal={Nature Immunology},
  • E. Wherry
  • Published 1 June 2011
  • Biology, Medicine
  • Nature Immunology
T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged and T cell exhaustion has been defined in many… 
Molecular and cellular insights into T cell exhaustion
Recent advances that provide a clearer molecular understanding of T cell exhaustion are reviewed and reveal new therapeutic targets for persisting infections and cancer.
T-cell exhaustion in the tumor microenvironment
The updated understanding on the exhausted T cells in cancer and their potential regulatory mechanisms are overviewed and current therapeutic interventions targeting exhausted T Cells in clinical trials are discussed.
Genomic and epigenomic perspectives of T-cell exhaustion in cancer
The genomic and epigenomic landscape of T-cell exhaustion in cancer is discussed and the relevant therapeutic interventions for T- cell exhaustion in clinical trials are introduced.
Defining ‘T cell exhaustion’
In this Viewpoint article, 18 experts in the field tell us what exhaustion means to them, ranging from complete lack of effector function to altered functionality to prevent immunopathology, with potential differences between cancer and chronic infection.
T‐cell exhaustion due to persistent antigen: Quantity not quality?
Several recent reports on T‐cell exhaustion are discussed, including one in this issue of the European Journal of Immunology where Richter et al. examine the importance of the amount of persistent antigen versus the cell type presenting it to induce CD8+ T‐ cell exhaustion.
CD8+ T cell exhaustion
T cell exhaustion is often associated with inefficient control of persisting infections and cancers, but re-invigoration of exhausted T cells with inhibitory receptor blockade can promote improved immunity and disease outcome.
Epigenetic Determinants of CD8+ T Cell Exhaustion
T cell exhaustion is a stable epigenetic state that is not rescued by common treatment modalities, and new strategies to modulate T cell exhaustion are sought.
T-cell exhaustion in allograft rejection and tolerance
Preventing or reversing T-cell exhaustion may lead to prevention of transplant tolerance or triggering of rejection; therefore, caution should be exercised in the use of agents blocking inhibitory receptors for the treatment of chronic viral infections or tumors in transplant recipients.


Effector CD8 T Cell Development: A Balancing Act between Memory Cell Potential and Terminal Differentiation1
Insights into how these equally essential processes are balanced to enhance health and longevity are discussed and what factors control effector T cell expansion, differentiation, and memory cell formation are discussed.
Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection
It is shown that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors, and regulation of T cell exhaustion by various inhibitory pathways was nonredundant.
Molecular signature of CD8+ T cell exhaustion during chronic viral infection.
CD8 T cell dysfunction during chronic viral infection.
Restoring function in exhausted CD8 T cells during chronic viral infection
It is found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the ‘helpless’ CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load.
T-bet represses expression of PD-1 and sustains virus-specific CD8 T cell responses during chronic infection
It is demonstrated that the transcription factor T-bet regulated the exhaustion of CD8+ T cells and the expression of inhibitory receptors and suggested therapeutic opportunities involving higher T-Bet expression during chronic infection.
Chronic Antigen Stimulation Alone Is Sufficient to Drive CD8+ T Cell Exhaustion1
A system of chronic Ag stimulation using murine influenza A virus is created that leads to exhaustion and functional disability of virus-specific CD8+ T cells, in the absence of high viral titers, sustained proinflammatory cytokine production and lymphocyte infection.
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
It is found that T cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) in mice bearing solid tumors and combined targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone.
Intrinsic Functional Dysregulation of CD4 T Cells Occurs Rapidly following Persistent Viral Infection
It is illustrated that virus-specific CD4 T cells are functionally inactivated early during the transition into viral persistence and fail to produce effector cytokines, thereby compromising an efficient and effective antiviral immune response.
Impact of Epitope Escape on PD-1 Expression and CD8 T-Cell Exhaustion during Chronic Infection
The data suggest that optimal strategies for vaccination should induce high-magnitude broadly specific T-cell responses that prevent cytotoxic T-lymphocyte escape and highlight the need to evaluate the function of vaccine-induced T cells in the context of antigens presented during virus persistence.