Reactivation of quiescent autoreactive T cells in experimental autoimmune encephalomyelitis as a model for multiple sclerosis
First, we wanted to test whether the autoreactive T cells in anti-VLA-4 antibody (PS/2 mAb) treated mice could be reactivated by microbial components and induce relapses in experimental autoimmune encephalomyelitis (EAE). By testing PS/2 mAb in both active and passive immunization EAE mouse models, we found that (1) pertussis toxin induced mortality in PS/2 mAb treated mice and CD4+ T cells were required; (2) combination of TLR ligands led to suppressive effects on clinical EAE and decreased autoantigen specific T cell cytokine responses.
In the second project, we wanted to determine whether macrophage migration inhibitory factor (MIF) played a role in resistance to glucocorticoids (GCs) treatment in EAE. We found that treatment of MIF knockout (MIF KO) mice with Dexamethasone (Dex) was substantially more efficacious as compared with Wt mice. In contrast, autoantigen-induced cytokine production by T cells was only partially suppressed by Dex and slightly affected by MIF. Importantly, Dex profoundly inhibited upregulation of the transcription factor T-bet in antigen-stimulated MIF KO CD4+ T cells as compared with Wt T cells.
The third project investigated the role of the transcription factor AIRE for the induction of autoreactive T cells in humanized HLA transgenic mice. To address this issue we generated aire knockout mice (aire-/-). The results show that aire-/- mice that lacked MHC Class II molecules had lower body weight and exhibited a higher percentage of CD8+ T cells. Infiltrates composed of CD11c+ cells and CD8 + T cells were found in the organs of aire-/-Ia-/- mice, especially in lung, liver and pancreas. The aire-/-Ia-/- model can be used to study CD8+ T cell mediated spontaneous autoimmune disease, such as type 1 diabetes.