Regulatory T cells and asthma

Abstract

Asthma is a chronic disease of airway inflammation due to excessive T helper cell type 2 (Th2) response. Present treatment based on inhalation of synthetic glucocorticoids can only control Th2-driven chronic eosinophilic inflammation, but cannot change the immune tolerance of the body to external allergens. Regulatory T cells (Tregs) are the main negative regulatory cells of the immune response. Tregs play a great role in regulating allergic, autoimmune, graft-versus-host responses, and other immune responses. In this review, we will discuss the classification and biological characteristics, the established immunomodulatory mechanisms, and the characteristics of induced differentiation of Tregs. We will also discuss the progress of Tregs in the field of asthma. We believe that further studies on the regulatory mechanisms of Tregs will provide better treatments and control strategies for asthma.

Keywords: Regulatory T cell; Asthma; Transforming growth factor β (TGF-β); Interleukin 10 (IL-10); IL-35.

Fig. 1

Classification of regulatory T cells Major characteristics of subsets of CD4⁺ regulatory T cells (Tregs) based on cell-surface markers and immunosuppressive cytokine secretion. nTreg: natural Treg; iTreg: induced Treg; Th: T helper cell; Tr1: T-regulatory cell type 1; TGF-β: transforming growth factor β; IL: interleukin

Fig. 2

Suppression mechanisms of Tregs Tregs suppress effector T cells by multiple mechanisms: (1) Tregs produce immunosuppressive cytokines (IL-10, IL-35, and TGF-β); (2) Tregs induce cell death via granzyme and perforin; (3) Tregs transfer cAMP to effector T cells which generate immunosuppressive adenosine; (4) Tregs inhibit T cell-activation by APCs through downregulating costimulatory molecules in APCs via CTLA-4; (5) Tregs consume cytokine IL-2 through IL-2R (CD25) which is required for T cell differentiation. TGF-β: transforming growth factor-β; cAMP: cyclic adenosine monophosphate; APC: antigen-presenting cell; Treg: regulatory T cells; CTLA-4: cytotoxic T lymphocyte-associated antigen-4; IL: interleukin

Fig. 3

Possible mechanism of instability of Treg differentiation In some disease conditions, iTregs differentiate into pathogenic T cells. Site 790 mutation in the mouse IL-4Rα gene activates STAT6 through IL-4 and IL-13, which makes mice more susceptible to allergic diseases. Site 576 mutation in the mouse IL-4Rα gene increases both IL-4 and IL-6 secretion. IL-6 promotes the differentiation of iTregs towards Th17 cells and ultimately leads to a mixed Th2-Th17 immune response in asthma. APC: antigen-presenting cell; TGF-β: transforming growth factor-β; iTreg: induced regulatory T cell; Th: T helper cell; IL: interleukin

Fig. 4

Induction of Tregs in vivo and in vitro Both sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) can increase differentiation of Tregs. Intestinal probiotics induce Tregs through Toll-like receptor 2 (TLR2) pathway or G protein-coupled receptor 43 (GPCR43) pathway. Some drugs, methimazole, rapamycin, and vitamin D₃ (VitD₃), can improve the suppression function of Tregs. Transplantation of antigen-modified iTregs expanded in vitro may be a promising treatment to asthma