Abstract
Experimental autoimmune uveitis (EAU) is a CD4+ T cell–mediated organ-specific autoimmune disease and has been considered as a model of human autoimmune uveitis. Dracocephalum heterophyllum (DH) is a Chinese herbal medicine used in treating hepatitis. DH suppressed the production of inflammatory cytokines through the recruitment of myeloid-derived suppressor cells (MDSCs) to the liver. However, it remains elusive whether DH can directly regulate CD4+ T cell biology and hence ameliorates the development of CD4+ T cell–mediated autoimmune disease. In the current study, we found that DH extract significantly suppressed the production of pro-inflammatory cytokines by CD4+ T cells. Further study showed that DH didn’t affect the activation, differentiation, and apoptosis of CD4+ T cells. Instead, it significantly suppressed the proliferation of conventional CD4+ T cells both in vitro and in vivo. Mechanistic study showed that DH-treated CD4+ T cells were partially arrested at the G2/M phase of the cell cycle because of the enhanced inhibitory phosphorylation of Cdc2 (Tyr15). In addition, we demonstrated that treatment with DH significantly ameliorated EAU in mice through suppressing the proliferation of autoreactive antigen specific CD4+ T cells. Taken together, the current study indicates that DH-mediated suppression of CD4+ T cell proliferation may provide a promising therapeutic strategy for treating CD4+ T cell–mediated diseases.
Highlights
Experimental autoimmune uveitis (EAU) is an animal disease model of human posterior autoimmune uveitis and can be induced in susceptible animals by immunization with retinal antigens (1)
Our results showed that the number of BrdU-positive CD4+ T cells from Peyer’s patches (PP), intestinal epithelial cells and lamina propria cells (LP) was greatly decreased when mice were treated with Dracocephalum heterophyllum (DH) (Figure 5D)
Using EAU mouse model, our current study revealed a novel mechanism of DH-mediated suppression of T-cell function, i.e., suppressing CD4+ T-cell proliferation
Summary
Experimental autoimmune uveitis (EAU) is an animal disease model of human posterior autoimmune uveitis and can be induced in susceptible animals by immunization with retinal antigens (1). EAU resembles the key immunological characteristics of autoimmune uveitis in humans, as both are CD4+ T cell–mediated (2–4). The proliferation and differentiation of autoreactive retinal antigen-specific CD4+ T cells is the major cause of the initiation and progression of EAU (5, 6). Among different types of CD4+ T cells, IFN-g-producing Th1 cells and IL-17–producing Th17 cells were implicated as the major contributors to the progression of EAU (7). Since T cells are central regulators of the immune response, it is essential to maintain a normal T cell homeostasis, as its deregulation can lead to immunodeficiency or autoimmunity (11–13)
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