Inflammatory bowel diseases
Microbiota-reactive CD4 T memory (TM) cells are generated during intestinal infections and inflammation, and can potentially serve as a reservoir for pathogenic CD4 T effector (TE) cells, thus driving the progression of inflammatory bowel diseases (IBD). Unlike TE cells, TM cells keep a low rate of metabolism unless they are activated by re-encountering cognate antigens. Here we show that microbiota flagellin-specific CD4 T cell activation plus simultaneous metabolic inhibition via mTORC and AMPK resulted in CD4 naïve and memory T cell death and anergy, but greatly enhanced the induction of CD4 regulatory T (Treg) cells with strong suppressive function. This metabolic inhibition treatment successfully prevented colitis development in the CBir1 TCR Tg CD4 T cell transfer model. CBir1 flagellin-specific CD4 T cells, especially the pathogenic TE subsets, were decreased 10 fold in the intestinal lamina propria. Furthermore, using this metabolic inhibition strategy, we were able to prevent microbiota flagellin-specific TM cell formation upon initial antigen encounter, and ablate pre-existing TM cells upon re-activation in mice. In both instances Treg cells were significantly elevated. Human microbiota flagellin-specific CD4 T cells isolated from patients with Crohn’s disease, stimulated with flagellin antigens plus metabolic inhibitor rapamycin, were ablated in a similar manner with half of the antigen-specific T cells undergoing apoptosis. These results indicate that metabolic inhibition of activated microbiota-specific CD4 T cells is an effective way to eliminate pathogenic CD4 TM cells and to induce Treg cells that provide antigen-specific and bystander suppression, serving as a promising immunotherapy for IBD.