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Modulation of regulatory T cell function and stability by co-inhibitory receptors

Nature Reviews Immunology volume 20, pages 680–693 (2020)Cite this article

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Abstract

Regulatory T (Treg) cells constitute a dynamic population that is essential for controlling immune responses in health and disease. Defects in Treg cell function and decreases in Treg cell numbers have been observed in patients with autoimmunity and the opposite effects on Treg cells occur in cancer settings. Current research on new therapies for these diseases is focused on modulating Treg cell function to increase or decrease suppressive activity in autoimmunity and cancer, respectively. In this regard, several co-inhibitory receptors that are preferentially expressed by Treg cells under homeostatic conditions have recently been shown to control Treg cell function and stability in different disease settings. These receptors could be amenable to therapeutic targeting aimed at modulating Treg cell function and plasticity. This Review summarizes recent data regarding the role of co-inhibitory molecules in the control of Treg cell function and stability, with a focus on their roles and potential therapeutic use in autoimmunity and cancer.

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Fig. 1: Summary of differences in Treg cells found in autoimmunity and cancer.
Fig. 2: Intrinsic and extrinsic functions of Treg cell co-inhibitory receptors.

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Authors and Affiliations

  1. Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA

    Liliana E. Lucca

  2. Faculty of Medicine, Imperial College London, London, UK

    Margarita Dominguez-Villar

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  1. Liliana E. Lucca
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Glossary

Co-inhibitory receptors

A family of surface receptors that attenuate and tune activation signals. Triggering of these receptors can result in heightened thresholds for T cell activation, shaping of effector responses and resolution of inflammation. Their expression is well characterized in T cells but not exclusive to immune populations.

Neuropilin 1

(NRP1). One of two members (NRP1 and NRP2) of a receptor family originally identified as class III semaphorin co-receptors in the nervous system, and further shown to be expressed in other cell types, including endothelial cells and tumour cells, as a receptor for vascular endothelial growth factors and other growth factors.

Pre-autoimmune disease

Preclinical systemic syndrome characterized by signs and symptoms that do not meet the diagnostic criteria of canonical autoimmune diseases but include the presence of autoantibodies.

Type 1 cytokines

Pro-inflammatory cytokines produced by CD4+ T helper 1 cells and CD8+ type 1 cytotoxic T cells, including IL-2, interferon-γ and tumour necrosis factor.

Indoleamine 2,3-dioxygenase

Haem-containing enzyme that catalyses the rate-limiting O2-dependent oxidation of l-tryptophan to N-formylkynurenine.

Warburg reaction

High glycolytic rate followed by lactic acid fermentation even in aerobic conditions. It has been described in tumour cells and more recently in CD8+ T cells as the preferential metabolic pathway for ATP synthesis, despite being less energy-efficient than oxidative phosphorylation.

GIT–PAK–PIX complex

Intracellular protein complex required for the dissociation of focal adhesions and for cellular motility.

Focal adhesions

Large supramolecular complexes that contain structural proteins involved in attachment to the extracellular matrix by mechanical force and regulatory signals.

Follicular Treg cells

Subpopulation of regulatory T (Treg) cells that function in lymphoid follicles and germinal centres to restrict and shape the maturation of B cell responses. Characterized by the expression of FOXP3, CXCR5 and ICOS.

CARMA1–BCL-10–MALT1 signalosome

Signalling complex assembled in T cells in response to protein kinase Cθ (PKCθ) activation by the scaffolding protein CARMA1. Promotes activation of the AP-1, mechanistic target of rapamycin (mTOR) and classical nuclear factor-κB pathways.

Chimeric antigen receptor

A B cell receptor-derived chimeric receptor that delivers a stimulatory signal upon binding of its cognate antigen without the need for presentation by MHC.

Immune-related adverse events

(IRAEs). Inflammatory events secondary to immunotherapy with immune checkpoint blocking agents.

Antibody-dependent cellular cytotoxicity

(ADCC). Mechanism whereby a cytotoxic immune cell lyses a target cell after recognizing specific antibodies bound to the surface of the target cell.

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Lucca, L.E., Dominguez-Villar, M. Modulation of regulatory T cell function and stability by co-inhibitory receptors. Nat Rev Immunol 20, 680–693 (2020). https://doi.org/10.1038/s41577-020-0296-3

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