The diverse functions of the PD1 inhibitory pathway
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...
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| Published in: | Nature reviews. Immunology Vol. 18; no. 3; pp. 153 - 167 |
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| Main Authors: | , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
01.03.2018
Nature Publishing Group |
| Subjects: | |
| ISSN: | 1474-1733, 1474-1741, 1474-1741 |
| Online Access: | Get full text |
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| Summary: | 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.
In this Review, the authors detail the complex expression patterns and regulation of programmed cell death protein 1 (PD1) and its ligands. The authors focus on the importance of understanding these pathways in order to optimize the efficiency and safety of immune checkpoint blockade in patients.
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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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23 |
| ISSN: | 1474-1733 1474-1741 1474-1741 |
| DOI: | 10.1038/nri.2017.108 |