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Regulatory T cells in the treatment of disease

Abstract

Regulatory T (Treg) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, Treg cells are compromised. Approaches to strengthen Treg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing Treg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, Treg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of Treg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating Treg cells in autoimmune disorders, transplantation and cancer.

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Figure 1: Steps in Treg cell development in vivo and in vitro.
Figure 2: Therapeutic approaches to alter Treg cells in autoimmune diseases and transplantation.
Figure 3: The production of therapeutic Treg cells.

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Acknowledgements

The authors' work was supported by US National Institutes of Health (NIH) grants AI42269, R37AI49954, AI068787, AI085567 and AR064350 (G.C.T.) and R21-CA195334, R01-AI131648 and the Sylvester Comprehensive Cancer Center at the University of Miami (T.R.M.).

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Correspondence to Amir Sharabi, David Klatzmann or George C. Tsokos.

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Competing interests

G.C.T. is a consultant for Johnson & Johnson and a science advisory board member for Abpro and Silicon Therapeutics (appointments that are not related to the work discussed herein). D.K. is an inventor on a patent application claiming low-dose IL-2 for therapy of autoimmune diseases, which is owned by his academic institution and licensed to ILTOO Pharma; D.K. advises for and holds shares in ILTOO Pharma. The University of Miami and T.R.M. have a patent pending (WO2016022671A1) on IL-2/CD25 fusion proteins that has been licensed exclusively to Bristol-Myers Squibb and have a collaboration and sponsored research & licensing agreement with Bristol-Myers Squibb. A.S., M.G.T. and Y.D. declare no competing interests.

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Glossary

Self-tolerance

The inability to respond to self-antigens.

CD4+ T cells

T cells that recognize peptides presented by major histocompatibility complex class II molecules and provide help to B cells to produce antibodies or to CD8+ cells to produce cytotoxic responses.

Effector T cells

(Teff cells). Short-lived activated cells that defend the body in an immune response.

T helper 1 cells

(TH1 cells). Cells that produce interleukin 2, interferon-γ and tumour necrosis factor and are pro-inflammatory.

T helper 17 cells

(TH17 cells). Cells that produce interleukin-17 and play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; they also propagate autoimmune and inflammatory pathology.

Co-stimulatory molecule

A membrane-bound or secreted product that is required for co-stimulation. This second signal (in addition to T cell receptor engagement) from an antigen-presenting cell to a T cell allows the T cell to become activated and produce cytokines. CD28 (on T cells) is the best known example.

Antigen-presenting cells

(APCs). Cells that display antigen complexed with major histocompatibility complex molecules on their surfaces, which they present to T cells.

Dendritic cells

(DCs). Cells that are named for their surface projections (which resemble the dendrites of neurons). They continuously sample the environment for antigen, which they process and present to T cells.

CD8+ T cells

Cytotoxic T cells that recognize peptides presented by major histocompatibility complex class I molecules.

Natural killer (NK) cells

Cytotoxic lymphocytes critical to the innate immune system that provide rapid responses to viral infection and respond to tumour formation. They express an array of activating and inhibitory receptors and produce interferon-γ.

T helper 2 cells

(TH2 cells). They promote allergic responses and provide help to B cells. Cells that can also promote resolution of inflammation and produce interleukin 4 (IL-4), IL-5, IL-6 and IL-10.

T follicular helper cells

(TFH cells). Antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleens and Peyer's patches.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). In this process, targeted cells become coated with antibody, and are then lysed by effector cells that have cytolytic activity and specific immunoglobulin crystallizable fragment (Fc) receptors. Lysis requires direct cell-to-cell contact and does not involve complement.

Complement-mediated cytotoxicity

A process that leads to the lysis of cells coated with immunoglobulin, a marker that is able to activate complement.

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Sharabi, A., Tsokos, M., Ding, Y. et al. Regulatory T cells in the treatment of disease. Nat Rev Drug Discov 17, 823–844 (2018). https://doi.org/10.1038/nrd.2018.148

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