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Eradicating microbiota-reactive effector T cells
Dysfunctional CD4+ T cell responses to gut microbiota antigens are the prime driver of inflammatory bowel disease. Patients with Crohn’s disease often exhibit both antibody and T cell responses targeting antigens from gut bacteria, especially flagellins. Zhao et al. developed a two-pronged strategy to weed out flagellin-reactive CD4+ T cells. Combined treatment using a metabolic inhibitor blocking the mTOR complex and induced T cell activation with an engineered peptide including flagellin epitopes achieved ablation of memory T cells in mouse models of colitis. The same combined approach also enabled purging of pathogenic T cells found in the blood of patients with Crohn’s disease. These findings support moving this line of investigation into human trials aimed at selective ablation of effector T cells causing Crohn’s disease.
Abstract
Microbiota-reactive CD4+ T memory (TM) cells are generated during intestinal infections and inflammation, and can revert to pathogenic CD4+ T effector (TE) cells, resulting in chronicity of inflammatory bowel disease (IBD). Unlike TE cells, TM cells have a low rate of metabolism unless they are activated by reencountering cognate antigen. Here, we show that the combination of cell activation and metabolic checkpoint inhibition (CAMCI), by targeting key metabolic regulators mTORC and AMPK, resulted in cell death and anergy, but enhanced the induction of the regulatory subset. Parenteral application of this treatment with a synthetic peptide containing multiple flagellin T cell epitopes (MEP1) and metabolic inhibition successfully prevented the development of CD4+ T cell–driven colitis. Microbiota-specific CD4+ T cells, especially the pathogenic TE subsets, were decreased 10-fold in the intestinal lamina propria. Furthermore, using the CAMCI strategy, we were able to prevent antigen-specific TM cell formation upon initial antigen encounter, and ablate existing TM cells upon reactivation in mice, leading to an altered transcriptome in the remaining CD4+ T cells after ablation. Microbiota flagellin–specific CD4+ T cells from patients with Crohn’s disease were ablated in a similar manner after CAMCI in vitro, with half of the antigen-specific T cells undergoing cell death. These results indicate that parenteral activation of microbiota-specific CD4+ T cells with concomitant metabolic inhibition is an effective way to ablate pathogenic CD4+ TM cells and to induce T regulatory (Treg) cells that provide antigen-specific and bystander suppression, supporting a potential immunotherapy to prevent or ameliorate IBD.
- Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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