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Next-generation regulatory T cell therapy


Regulatory T cells (Treg cells) are a small subset of immune cells that are dedicated to curbing excessive immune activation and maintaining immune homeostasis. Accordingly, deficiencies in Treg cell development or function result in uncontrolled immune responses and tissue destruction and can lead to inflammatory disorders such as graft-versus-host disease, transplant rejection and autoimmune diseases. As Treg cells deploy more than a dozen molecular mechanisms to suppress immune responses, they have potential as multifaceted adaptable smart therapeutics for treating inflammatory disorders. Indeed, early-phase clinical trials of Treg cell therapy have shown feasibility, tolerability and potential efficacy in these disease settings. In the meantime, progress in the development of chimeric antigen receptors and in genome editing (including the application of CRISPR–Cas9) over the past two decades has facilitated the genetic optimization of primary T cell therapy for cancer. These technologies are now being used to enhance the specificity and functionality of Treg cells. In this Review, we describe the key advances and prospects in designing and implementing Treg cell-based therapy in autoimmunity and transplantation.

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Fig. 1: Registered clinical trials using regulatory T cells.
Fig. 2: Regulatory T cells as living drugs.
Fig. 3: Timeline of events in the development of regulatory T cell therapy.
Fig. 4: Redirecting regulatory T cells by engineering T cell receptors.
Fig. 5: Methods for delivering genetic material to engineer regulatory T cells.


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L.M.R.F. is the Jeffrey G. Klein Family Diabetes Fellow. Y.D.M. was supported by the Swiss National Science Foundation (Advanced Postdoctoral Mobility grant no. P300PB_174500). J.A.B. acknowledges support of the Sean N. Parker Autoimmune Laboratory. The authors apologize to all of the researchers whose work they could not cite owing to reference number limitations.

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All authors contributed to all aspects of the article. L.M.R.F. and Y.D.M. contributed equally.

Corresponding authors

Correspondence to Jeffrey A. Bluestone or Qizhi Tang.

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Competing interests

J.A.B. and Q.T. acknowledge support from the Juvenile Diabetes Research Foundation, Caladrius Biosciences, Becton, Dickinson and Company (BD), Juno Therapeutics and Pfizer. L.M.R.F. has patents and pending patents on genome editing of T cells, haematopoietic stem cells and pluripotent stem cells. J.A.B. and Q.T. have patents and pending patents on polyclonal and antigen-specific regulatory T cells and consult for Third Rock Ventures and Juno Therapeutics in this area. J.A.B. serves on the board of Pfizer. Y.D.M. has no competing interests.

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Peripheral mechanism for tolerizing T cells in which they are blocked at the G1 phase of the cell cycle and unable to proliferate.

Systemic lupus erythematosus

A group of chronic autoimmune disorders defined by inflammation affecting various connective tissues in various organs, including the skin, joints, kidney, lung, nervous system or haematopoietic system.

Autoimmune polyendocrine syndromes

A group of diseases characterized by loss of tolerance and inflammation in endocrine glands, including the thyroid, parathyroid and adrenal glands or the pancreas. They are frequently associated with alopecia, vitiligo, coeliac disease and autoimmune gastritis.

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome

Specific form of an inherited autoimmune polyendocrine syndrome characterized by a mutation or mutations in the master transcription factor forkhead box protein P3 gene (FOXP3), leading to regulatory T cell dysfunction.

Type 1 T helper cell

(TH1 cell). A type of CD4+ T helper cell expressing TBET as a key transcription factor and defined by its ability to preferentially secrete interferon-γ and induce CD8+ T cell and macrophage activation.

Type 2 T helper cell

(TH2 cell). A type of CD4+ T helper cell expressing GATA3 as a key transcription factor and defined by its ability to preferentially secrete Il-4, IL-5 and IL-13 and promote B cell expansion and antibody class switching.

IL-17-producing T helper cell

(TH17 cell). A type of CD4+ T helper cell expressing RORɣt as a key transcription factor and defined by the production of IL-17, a cytokine important for maintaining mucosal barrier integrity and clearing helminth infections.

Mixed lymphocyte reactions

In vitro tests consisting of mixing different subsets of T cells together in the presence of antigen-presenting cells.

K562 cell-based artificial APCs

K562 cells are an immortalized human leukocyte antigen (HLA)-deficient cell line initially isolated from a chronic myelogenous leukaemia. Artificial antigen-presenting cells (APCs) are K562 cells that have been gene edited to express CD80 and/or CD86 and specific HLA alleles to function as APCs.


Short polypeptide connecting the A chain of proinsulin to the B chain. After packaging in vesicles in pancreatic beta cells, C-peptide is removed from proinsulin, leaving the A chain and the B chain linked by a disulfide bridge. Blood C-peptide levels are used to monitor endogenous insulin expression in patients with diabetes.

Amyotrophic lateral sclerosis

Neurodegenerative disorder characterized by the progressive loss of motor neurons, causing muscle weakness, atrophy and eventually death.

Pemphigus vulgaris

Group of skin disorders characterized by the formation of blisters induced by autoantibodies targeting intercellular adhesion molecules on keratinocytes.

Guillain–Barré syndrome

Immune-mediated polyneuropathy, usually started after an infection, sharing cross-reactive epitopes with peripheral nerves (myelin or axonal membrane).

Alzheimer’s disease

Neurogenerative disorder leading to progressive dementia associated with the accumulation of amyloid-β plaques in nervous cells of the central nervous system.

Marginal zone

High-transit area constituted by B cells, macrophages, dendritic cells and granulocytes, interposed between lymphoid tissues and the circulation, serving as a sentinel for blood-borne antigens.

HLA restriction

The presentation of a peptide by a specific human leukocyte antigen (HLA) to a T cell’s receptor.

Complementarity-determining regions

Parts of the variable chain of the T cell receptor or of an antibody that determine specificity to their cognate antigen.

Tonic signalling

Low level of signalling independent of activating antigen in resting T cells.

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Ferreira, L.M.R., Muller, Y.D., Bluestone, J.A. et al. Next-generation regulatory T cell therapy. Nat Rev Drug Discov 18, 749–769 (2019).

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