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Molecular and cellular insights into T cell exhaustion
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Journal Article
Molecular and cellular insights into T cell exhaustion
2015
Overview
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.
Exhausted T cells display a phenotype characterized by progressive loss of function, and they can develop following exposure to persistent antigen and/or inflammatory signals during chronic viral infections or cancer. The authors describe the molecular mechanisms of T cell exhaustion and how the exhausted phenotype is different from other dysfunctional states of T cells.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
