Antigen clearance at the peak of the primary immune response induces experimental autoimmune encephalomyelitis.

Autoimmune demyelinating diseases can be induced by an immune response against myelin peptides; however, the exact mechanism underlying the development of such diseases remains unclear. In experimental autoimmune encephalomyelitis, we found that the clearance of exogenous myelin antigen at the peak of the primary immune response is key to the pathogenesis of the disease. The generation of effector T cells requires continuous antigen stimulation, whereas redundant antigen traps and exhausts effector T cells in the periphery, which induces resistance to the disease. Moreover, insufficient antigenic stimulation fails to induce disease efficiently owing to insufficient numbers of effector T cells. When myelin antigen is entirely cleared, the number of effector T cells reaches a peak, which facilitates infiltration of more effector T cells into the central nervous system. The peripheral antigen clearance initiates the first wave of effector T cell entry into the central nervous system and induces chronic inflammation. The inflamed central nervous system recruits the second wave of effector T cells that worsen inflammation, resulting in loss of self-tolerance. These findings provide new insights into the mechanism underlying the development of autoimmune demyelinating diseases, which may potentially impact future treatments.

[Mechanism of immune tolerance induced by soluble myelin oligodendrocyte glycoprotein in mice with experimental autoimmune encephalomyelitis].

Objective To explore the mechanism of immune tolerance induced by soluble MOG35-55 (MOG) peptide in mice with experimental autoimmune encephalomyelitis (EAE). Methods EAE mice were randomly divided into three groups, MOG, OVA and control groups, which were injected intraperitoneally with MOG, OVA peptide and PBS, respectively, from day 6 to day 16 after EAE induction. Lymphocytes in the spleen and CNS were enumerated and their phenotypes and function were analyzed by flow cytometry to explore the role of T cell migration in MOG-induced EAE tolerance. Next, CD11b+ antigen presenting cells (APCs) in the spleen and CNS infiltration were analyzed by flow cytometry to evaluate their maturation, and the role of mature APCs in blocking MOG-CD4+ T cells trafficking to CNS was determined by immunofluorescence technique. Results MOG trapped effector T cells in the spleen and protected mice from EAE. MOG triggered the maturation of splenic APCs, while prevented the maturation of CNS-infiltrating APCs. MOG-loaded APCs could interact with MOG reactive CD4+ T cells and limit their migration. Conclusion MOG can protect mice from EAE by inducing the maturation of splenic APCs that interact with MOG-T cells and trap them in the periphery.

The immune response is a prerequisite for the development of CD4+Foxp3+ regulatory T cells in transplantation.

CD4+Foxp3+ regulatory T cells (Tregs) are critical in maintaining the peripheral tolerance and homeostasis of the immune system, yet their development and role in transplantation are poorly understood. Here we show that the levels of Tregs in neonatal transplant tolerant mice are similar to the levels in naive mice when they are kept in a state of homeostasis devoid of an immune response. An increased frequency of Tregs was observed only in recipients with allograft rejection, in naive mice that received alloantigens, or in tolerant mice adoptively transferred with alloreactive T cells. Even though an antigen-specific immune response is a prerequisite for the development of Tregs, both antigen-specific and nonspecific Tregs are generated in this process. We conclude that Tregs are induced and function in an inflammatory environment and in a negative feedback loop.