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Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Nature Reviews Immunology volume 16, pages 149–163 (2016)Cite this article

Subjects

Key Points

  • CD4+ T cells are plastic, being able to both acquire distinct functions to combat specific pathogens and redirect their functions in response to changing circumstances or different pathogens.

  • T cell plasticity is an inherent characteristic of T cell responses that provides advantages to the host for protective immunity and immune control.

  • Extracellular cues from the environment drive T cell reprogramming, but they do so within the framework of cytosolic signalling, metabolic and epigenetic circuitry that is established in the cell to stabilize polarized T cell functions.

  • T cell plasticity is widely observed in immune-based diseases, such as autoimmunity and cancer, and may contribute to disease pathology.

  • There is potential to modulate immunity by targeting key regulatory nodes that programme inflammatory versus regulatory functions in T cells.

Abstract

CD4+ T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4+ T cell plasticity by examining the molecular mechanisms that regulate it — from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Figure 1: Polarized CD4+ T cell subsets.
Figure 2: The integration of signals at many levels in T cells regulates plasticity.
Figure 3: Cytokine-driven T cell plasticity.
Figure 4: The PI3K–AKT–mTOR pathway and metabolic programmes converge to regulate the plasticity of inflammatory versus regulatory T cells.
Figure 5: Mechanisms of gene regulation in T cell plasticity.

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Acknowledgements

The authors thank A. Abbas, K. M. Ansel, R. Locksley, L. Turka and members of the laboratory for their helpful comments and feedback during the preparation of this Review. This work was supported by the Sean N. Parker Autoimmune Research Laboratory, the Juvenile Diabetes Research Foundation (JDRF; 2-SRA-2014-150), the US National Institutes of Health (NIH; R01 AI046643, U01 AI102011) and the Helen Hay Whitney Foundation (to M.D.).

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  1. Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, 94143, California, USA

    Michel DuPage & Jeffrey A. Bluestone

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Glossary

mTOR complex 1

(mTORC1). A complex consisting of: mammalian target of rapamycin (mTOR), which is a serine/threonine kinase; regulatory-associated protein of mTOR (RAPTOR); proline-rich AKT1 substrate of 40 kDa (PRAS40), which is an mTORC1 inhibitor; mLST8, which is of unknown function; and DEP domain-containing mTOR-interacting protein (DEPTOR), which is an mTOR inhibitor.

mTORC2

A complex composed of mammalian target of rapamycin (mTOR), mLST8 and the adaptor proteins rapamycin-insensitive companion of mTOR (RICTOR) and stress-activated MAP kinase-interacting protein 1 (SIN1).

Tricarboxylic acid cycle

(TCA cycle). This pathway (also known as the Krebs cycle or citric acid cycle) catalyses the oxidation of acetyl-CoA (from glucose or fatty acids or indirectly from amino acids) to generate NADH and FADH, which fuel the electron transport chain and thereby oxidative phosphorylation and ATP production. It also serves as a source of precursors for amino acid and lipid synthesis.

Innate lymphoid cells

Lymphoid cells that do not express unique antigen receptors derived from gene rearrangement or cell-surface markers that are characteristic of other immune cell lineages. However, in response to innate tissue-derived signals, they secrete cytokines that are associated with T helper cell subsets. They have important roles in innate immune responses to infectious microorganisms and in lymphoid tissue formation.

Long non-coding RNAs

(lncRNAs). A subset of non-coding RNAs that are greater than 200 nucleotides in length and distinct from other non-coding RNAs, such as tRNAs, rRNAs, snRNAs, small nucleolar RNAs (snoRNAs), and microRNAs. Although they are known to regulate gene expression, the mechanisms by which this is achieved is an active area of investigation.

Chimeric antigen receptor

(CAR). An artificial T cell receptor construct that consists of an extracellular single-chain antibody fragment that functions as the antigen-binding domain, together with transmembrane and intracellular signalling domains from the T cell receptor CD3 ζ-chain and/or from a co-stimulatory molecule such as CD28.

BET inhibitors

Inhibitors that bind the bromodomain and extraterminal (BET) motif of several bromodomain-containing proteins (BRDs), blocking their interaction with acetylated lysines on histones and preventing their promotion of transcription.

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DuPage, M., Bluestone, J. Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nat Rev Immunol 16, 149–163 (2016). https://doi.org/10.1038/nri.2015.18

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