Role of Treg cells in Autoimmune Disease
Deregulated T cell activity that results in the destruction of one’s own cells and tissues is the underlying cause of many autoimmune disorders such as lupus, type 1 diabetes, psoriasis and multiple sclerosis (MS). Self-targeting by cytotoxic T cells in these disorders can be due to increased activation of these cells, increased signaling from helper T cells, or regulatory T (Treg) cell inhibition. Tregs normally function to down-regulate effector T cell activity and proliferation to achieve self-tolerance, minimize cytotoxic effects to healthy cells, and maintain homeostasis. Impaired Treg activity contributes to autoimmune disorders and finding treatment strategies to re-activate these regulatory cells is a high priority. In a recent article in The Journal of Immunology, a team led by Dr. Panayotis Verginis at the Academy of Athens demonstrates that myelin immunization generates new, activated Tregs in mice with experimental autoimmune encephalomyelitis (EAE), a common mouse model for MS. These myelin-targeted Tregs impair both the recruitment and activity of inflammatory dendritic cells (iDC) and improve EAE phenotypes. These data provide a foundation for the development of new Treg-directed therapies which may provide new treatment alternatives to reset homeostasis in patients with autoimmune disorders.
Modulation of EAE with Immunogen-Stimulated Tregs
To generate antigen-specific Tregs in the context of autoimmune disorder, the researchers induced EAE in C57BL/6J (Stock# 000664) and BALB/cJ (Stock# 000651) mice that were pre-immunized with myelin oligodendrocyte glycoprotein (MOG35-55). Pre-immunized mice had less severe disease and a decreased onset compared to non-immunized mice. Further, CD4+ and CD8+ T cells, as well as dendritic cells, were reduced in spinal cord aspirates in immunized mice. Decreased numbers of effector immune cell types were concomitant with an increase in Tregs in both the local lymph nodes and in spinal cord aspirates. The contribution of these activated Tregs in ameliorating EAE symptoms was evaluated by inducing EAE in the DEREG (“depletion of regulatory T cell”) model, C57BL/6-Tg(Foxp3-DTR/EGFP)23.2Spar/Mmjax (MMRRC# 032050, JAX Stock# 011003). Following diphtheria toxin-induced depletion of myelin-specific Tregs in pre-immunized DEREG mice, T cell proliferation increased, secretion of inflammatory cytokines increased, and EAE disease characteristics returned. The authors also found that inhibiting suppressive Treg IL-10 signaling (following immunization and stimulation of EAE in IL-10-deficient B6.129P2-Il10tm1Cgn/J, Stock# 002251 mice), restored iDC recruitment to regional lymph nodes, thus promoting autoimmune signaling.
This study demonstrates that Treg cells can be activated in vivo to inhibit autoimmune signaling, and sheds light on which signals in particular might be exploited for the development of novel therapies. The study also improves our understanding of the complicated signals that silence Tregs in autoimmune disorders, which also may provide new insight into disease causes and treatment strategies.