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The diverse functions of the PD1 inhibitory pathway

This article has been updated

Key Points

  • Programmed cell death protein 1 (PD1) is an inhibitory receptor that is expressed by all T cells during activation. It regulates T cell effector functions during various physiological responses, including acute and chronic infection, cancer and autoimmunity, and in immune homeostasis.

  • PD1 often shows high and sustained expression levels during persistent antigen encounter, which can occur in the setting of chronic infections and cancer. In these settings, PD1 can limit protective immunity.

  • In addition to being expressed by conventional T cells, PD1 is expressed by regulatory T cells, B cells, natural killer cells and some myeloid cell populations. However, compared with conventional T cells, less is known about how PD1 inhibitory signals regulate these cell types.

  • Programmed cell death 1 ligand 1 (PDL1) shows broad expression on both haematopoietic and non-haematopoietic cells, positioning the PD1 pathway as a key regulator of immune cell functions in both secondary lymphoid organs and in non-lymphoid tissues.

  • PD1 limits the activation and function of potentially pathogenic self-reactive CD4+ and CD8+ T cells, and PDL1 can shield target organs from autoimmune attack.

  • Due to the diverse roles of the PD1 pathway in regulating host immunity, context is everything. In order to safely and effectively modulate the PD1 pathway therapeutically, the complex immunological status of the patient should be carefully considered.

Abstract

T cell activation is a highly regulated process involving peptide–MHC engagement of the T cell receptor and positive costimulatory signals. Upon activation, coinhibitory 'checkpoints', including programmed cell death protein 1 (PD1), become induced to regulate T cells. PD1 has an essential role in balancing protective immunity and immunopathology, homeostasis and tolerance. However, during responses to chronic pathogens and tumours, PD1 expression can limit protective immunity. Recently developed PD1 pathway inhibitors have revolutionized cancer treatment for some patients, but the majority of patients do not show complete responses, and adverse events have been noted. This Review discusses the diverse roles of the PD1 pathway in regulating immune responses and how this knowledge can improve cancer immunotherapy as well as restore and/or maintain tolerance during autoimmunity and transplantation.

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Figure 1: PD1 signalling and diversity of binding partners.
Figure 2: Roles of PD1 in acute infection, tolerance and cancer.
Figure 3: Use of PD1-based combination therapy to promote anticancer immunity.

Change history

  • 13 November 2017

    On page 5 of this manuscript, in the subsection titled 'PD1 ligands', the html and PDF versions originally contained the incorrect sentence "Cytokines are cru PDL2 expression (TABLE 1), with type I interferons and cial regulators of PDL1 and type II interferon being some of the most potent drivers of PDL1 expression6,48." This has now been corrected to "Cytokines are crucial regulators of PDL1 and PDL2 expression (TABLE 1), with type I interferons and type II interferon being some of the most potent drivers of PDL1 expression6,48." in the html and PDF versions of this manuscript.

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Acknowledgements

The authors thank J. Schenkel for helpful discussions and critical reading of the manuscript. The authors apologize to colleagues whose work was not cited in this Review owing to space constraints. This work was supported by grants from the US National Institutes of Health (P01 AI56299, AI 40614) (to A.H.S.) and the Evergrande Center for Immunological Diseases at Harvard Medical School and Brigham and Women's Hospital.

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The authors contributed equally to researching, writing and editing the review.

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Correspondence to Arlene H. Sharpe.

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Competing interests

A.H.S. is an inventor on patent numbers US 8552154 B2, US 8652465 B2 and US 9102727 B2, held by Emory University (Atlanta, Georgia, USA), Dana–Farber Cancer Institute (Boston, Massachusetts, USA), Brigham and Women's Hospital (Boston) and Harvard University (Cambridge, Massachusetts, USA), which cover the topic of PD1-directed immunotherapy.

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Glossary

Self-tolerance

Broadly refers to a series of mechanisms used by the body to limit the activation of self-reactive T cells and B cells to prevent these cells from targeting and destroying self tissues.

Central tolerance

Mechanisms of tolerance that occur in the central lymphoid organs (thymus for T cells, bone marrow for B cells). Mechanisms include negative selection (for both T cells and B cells), receptor editing (for B cells) and lineage deviation (for T cells).

Peripheral tolerance

Mechanisms of tolerance that occur in the periphery after full development of lymphocytes in the bone marrow or thymus and their egress from these sites. These mechanisms can occur during priming in the secondary lymphoid organs or in peripheral tissues.

Immune checkpoints

An alternative term for coinhibitory molecules, generally referring to inhibitory signals that immune cells must overcome to perform full effector functions.

Effector T cells

T cells that have recently encountered antigen and differentiated from a quiescent state to a fully activated state, a conversion that is accompanied by proliferation and acquisition of effector functions.

T cell exhaustion

Caused by chronic antigenic stimulation and exposure to chronic inflammation, T cell exhaustion results in a progressive loss of effector functions and potential over time. There are subsets of exhausted T cells that differ in their functionality.

Tolerant T cells

Self-reactive T cells that have been activated by cognate antigen but have been rendered hypofunctional to protect self tissues from destruction. Mechanisms include anergy, active suppression by regulatory T cells and suppression through programmed cell death protein 1 (PD1).

Regulatory T (Treg) cells

Generally refers to a subset of CD4+ T cells that expresses the transcription factor forkhead box protein P3 (FOXP3) and actively inhibits immune responses (through immunosuppressive cytokine production, modulating dendritic cell function, metabolic disruption and/or production of adenosine). Additional populations of Treg cells include CD8+ Treg cells, RORγt+FOXP3+ Treg cells and T regulatory type 1 (TR1) cells.

T follicular helper (TFH) cells

A subset of CD4+ T cells that expresses CXC-chemokine receptor 5 (CXCR5), BCL-6, programmed cell death protein 1 (PD1) and ICOS, localizes to the B cell follicle and provides help to B cells to generate productive humoral immune responses (through CD40 and IL-21).

T follicular regulatory (TFR) cells

A subset of regulatory T cells that expresses forkhead box protein P3 (FOXP3), CXCR5, BCL-6, B lymphocyte-induced maturation protein 1 (BLIMP1), programmed cell death protein 1 (PD1) and ICOS and that attenuates humoral immunity by controlling TFH cell and B cell functions.

Memory T cells

Long-lived populations of antigen-experienced T cells that persist after acute antigen is cleared. Compared with their naive counterparts, memory T cells are present in higher numbers, have a broader anatomical distribution and more rapidly differentiate into effector cells upon antigen re-encounter. Naive T cells are restricted to secondary lymphoid organs (SLOs), while central memory T cells can be found in SLOs, effector memory T cells circulate in blood and non-lymphoid tissues, and resident memory T cells permanently reside in either SLOs or non-lymphoid tissues.

DNA methylation

An epigenetic modification that results in transcriptional repression.

ATAC-seq

(Assay for transposase-accessible chromatin with high-throughput sequencing). A rapid and sensitive method of assaying chromatin accessibility that uses in vitro transposition of sequencing adaptors into open chromatin followed by high-throughput sequencing to determine the location of open chromatin.

Epigenetic regulation

A broad set of heritable changes in gene expression that occur independently of changes to the DNA sequence (for example, DNA methylation, histone modifications) that broadly defines the transcriptional capacity of a cell, dictating cell lineage, fate and effector potential.

Type I interferons

Type I interferons, such as IFNα and IFNβ, are generally produced in response to danger-associated signals such as Toll-like receptors and cytosolic nucleic acid sensors. Type I interferons are produced by most cells in the body and have a variety of immunostimulatory effects and innate antiviral effects during acute infection, including inhibition of translation. By contrast, persistent type I interferon signalling during chronic viral infection can promote immune dysfunction.

Type II interferon

IFNγ, a key T cell and natural killer cell effector molecule that drives myeloid activation, MHC class I and II processing and presentation, leukocyte trafficking and pathogen replication inhibition.

Adaptive resistance

Mechanisms by which a tumour adapts to tumour-specific immune responses, leading to the upregulation of immunosuppressive molecules, such as programmed cell death 1 ligand 1 (PDL1), in an attempt to evade host immunity.

Anergic T cells

A form of peripheral tolerance induced at priming, generally resulting from high levels of antigen being recognized with inadequate amounts of costimulation and/or inflammatory cytokines. Anergic T cells persist in a functionally hyporesponsive state, but functionality can be restored if proper signals are provided.

Neoantigen-specific T cell

A T cell that recognizes antigens in the tumour that have been mutated so that the antigen no longer resembles self antigens, theoretically making these antigens more immunogenic because they are less affected by central tolerance.

Immunogenicity

The ability of an antigen to stimulate an immune response; highly immunogenic antigens are generally recognized by the immune system as foreign (or distinct from self) and their recognition is accompanied by inflammation.

irRECIST

(Immune-related response evaluation criteria in solid tumours). Similar to RECIST, where a total of five malignant lesions, two per organ, are measured unidimensionally, with shared response criteria (complete response, partial response, stable disease and progressive disease defined), but the physician waits up to 12 weeks to confirm progressive disease to account for the flare effect.

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Sharpe, A., Pauken, K. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 18, 153–167 (2018). https://doi.org/10.1038/nri.2017.108

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