Biological function of type 1 regulatory cells and their role in type 1 diabetes

Abstract

The collapse of immune homeostasis induces type 1 diabetes (T1D). In T1D, uncontrolled immune attacks against islet β cells reduce insulin secretion, resulting in hyperglycaemia and various complications. Type 1 regulatory (Tr1) cell therapy is a promising approach for the treatment of T1D. Tr1 cells are a subset of regulatory T (Treg) cells that are characterised by high interleukin-10 secretion and forkhead box protein P3 non-expression. Tr1 cells are reduced and have impaired function in patients with T1D. Immunotherapy is used to treat various diseases, and Treg cells have been applied to treat T1D in animal models and clinical trials. However, the safety and efficacy of Tr1 cells in treating diabetes and other diseases remain unclear. In this review, we aim to investigate the identification and biological function of Tr1 cells and related studies on immune diseases; additionally, we discuss the feasibility, limitations, and possible solutions of Tr1 cell therapy in T1D. This review shows that T1D is caused by an immune imbalance where defective Tr1 cells fail to control effector T cells, leading to the destruction of islet β cells. However, Tr1 cell therapy is safe and effective for other immune diseases, suggesting its potential for treating T1D.

Keywords: Autoimmune disease; Biological function; Cell therapy; Type 1 diabetes; Type 1 regulatory cell.

Fig. 1

Suppressive mechanism of type 1 regulatory cells. Type 1 regulatory (Tr1) cells exert their immunosuppressive function through several mechanisms. The first immunosuppressive mechanism involves cytokines such as tumour growth factor (TGF)‐β, interleukin (IL)‐Tr1, and direct killing of effector or antigen-presenting cells (APCs) by perforin, granzyme B, or cell-to-cell interaction. The second immunosuppressive mechanism involves APCs and CTLA‐4. This mechanism includes decreased CD80/86 expression by APCs when binding to CTLA-4 expressed by activated Tr1 cells, leading to impaired APC maturation and reduced T cell proliferation. The third immunosuppressive mechanism involves Tr1 promoting the production of immunoglobulin (Ig) G4 by B cells via IL-10, TGF-β, and glucocorticoid-induced tumour necrosis factor (TNF) receptor-related protein (GITR)/GITR-L interaction. Lastly, Tr1 cells can suppress IL-1β production by macrophages by secreting IL-10.

Fig. 2

Recent shifts in regulatory T cells in type 1 diabetes research. With more profound insight into regulatory T cells in type 1 diabetes (T1D), Tr1 cells are considered more vital than FOXP3⁺ regulatory T (Treg) cells in preventing diabetes and inducing long-term immune tolerance.

Fig. 3

Idea map of Tr1 cell therapy in T1D. T1D is an incurable autoimmune disease induced by the collapse of immune homeostasis. Peripheral blood mononuclear cells (PBMCs) were collected from patients with T1D (a). The CD4⁺CD45RA-IL10⁺ gating strategy was used to sort Tr1 cells using an IL-10 capture assay (b). Two weeks of expansion of Tr1 stimulated by anti-CD3/CD28 beads and IL-2 and IL-10 (c). Secondary purification of Tr1 cells may improve the therapeutic effects and reduce side effects (d). Refusion of Tr1 into patients with T1D (e).