Review Article | Published:

Molecular and cellular insights into T cell exhaustion

Nature Reviews Immunology volume 15, pages 486499 (2015) | Download Citation


In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called 'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.

Key points

  • T cells exposed to persistent antigen and/or inflammatory signals in chronic infection or cancer can become 'exhausted', a state characterized by a hierarchical loss of effector functions and memory T cell properties, and by the expression of multiple inhibitory receptors.

  • T cell exhaustion prevents optimal control of infections and tumours, but modulating inhibitory pathways that are overexpressed in exhaustion can reverse this dysfunctional state and reinvigorate immune responses.

  • Exhausted T cells are a distinct lineage of differentiated T cells; these cells are phenotypically and mechanistically different from other dysfunctional states of T cells such as anergy and senescence.

  • Altered usage of transcription factors is a key feature of T cell exhaustion. Whereas transcription factors such as T-bet, EOMES (eomesodermin) and BLIMP1 (B lymphocyte-induced maturation protein 1) can have roles in other T cell populations, their expression pattern, target genes and functions in exhausted T cells are distinct.

  • Antigen-specific CD4+ T cells also progress to exhaustion during chronic infection. Although CD4+ and CD8+ T cell exhaustion share a core transcriptional signature, exhaustion of CD4+ T cells is distinct from that of CD8+ T cells, as each subset has different expression patterns of molecules such as inhibitory receptors and transcription factors.

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The authors thank the members of Wherry laboratory for discussions. In particular, they would like to thank J. Kurachi for technical assistance and figure preparation, and E. Stelekati and K. Pauken for helpful comments. The authors' work is supported by The Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid for Young Scientists (B) 22790453 to M.K.), the Uehara Memorial Foundation of Japan (M.K.) and the US National Institutes of Health (grants AI105343, AI112521, AI082630, AI095608 and HHSN266200500030C to E.J.W.).

Author information


  1. Department of Microbiology and Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, Pennsylvania 19104, USA.

    • E. John Wherry
    •  & Makoto Kurachi


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Competing interests

E.J.W. has a patent licensing agreement with Roche/Genentech on the PD1 pathway and is a member of the scientific advisory board of Surface Oncology. M.K. declares no competing interests.

Corresponding authors

Correspondence to E. John Wherry or Makoto Kurachi.


Effector memory T cells

A subset of memory T cells that resides in peripheral tissues and retains high levels of effector function such as the production of interferon-γ and granzymes.

Central memory T cells

A subset of memory T cells that expresses CD62L and CC-chemokine receptor 7 and resides mainly in the lymph nodes and spleen. These cells have high proliferative potential upon antigen re-encounter.

Lymphocytic choriomeningitis virus

(LCMV). A virus that induces a strong T cell response and therefore provides good mouse model of infection. Although they only differ by two nucleotides, the Armstrong strain of LCMV causes acute infection and the clone 13 strain causes chronic infection. As major antigenic epitopes are conserved between these two strains, the fate of antigen-specific T cells can be easily compared (that is, memory after infection with the Armstrong strain versus exhaustion after infection with the clone 13 strain).

Antigen-presenting cells

(APCs). T cells can be activated when antigen is displayed by major histocompatibility complexes (MHC restriction). This antigen presentation is largely executed by professional APCs, particularly dendritic cells. APCs also influence T cell differentiation by producing cytokines such as type I interferons and interleukin-12.

Senescent T cells

Cells that enter a terminal differentiation state owing to excessive cell replication. This state is associated with irreversible cell cycle arrest and telomere shortening.

Anergic T cells

An unresponsive state that is induced by suboptimal stimulation (that is, signal 1 without signal 2) at the time of priming by antigen.

Epigenetic landscape

Historically, this is proposed to refer to embryonic development and how genes might interact with their surroundings to lead to the expression of a certain phenotype. The current view of the epigenetic landscape is that overall epigenetic changes such as (but not limited to) DNA methylation and histone modifications, are accumulated genome wide and have strong impact on cellular differentiation.

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