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Inflammatory bowel diseases
Oral
Qing Zhao
Postdoctoral Fellow
The University of Alabama at Birmingham
Lennard Duck
The University of Alabama at Birmingham
Charles Elson
The University of Alabama at Birmingham
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.