Distinct Regulatory and Effector T Cell Metabolic Demands during Graft-Versus-Host Disease. Issue 1 (January 2020)

• Record Type: Journal Article
• Authors: Hippen, Keli L.; Aguilar, Ethan G.; Rhee, Stephanie Y.; Bolivar-Wagers, Sara; Blazar, Bruce R.
• Is Part Of: Trends in immunology. Volume 41:Issue 1(2020)
• Page Start: 77
• Page End: 91
• Publication Date: 2020-01
• Subjects: Treg -- Foxp3 -- GVHD -- microbiota -- glycolysis -- OXPHOS; Immunology -- Periodicals; 571.96
• DOI: 10.1016/j.it.2019.11.005
• Languages: English
• ISSNs: 1471-4906

Abstract

Abstract : Despite graft-versus-host disease (GVHD) prophylactic agents, the success and wider utilization of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by GVHD. Increasing donor graft regulatory T cell (Treg):effector T cell (Teff) ratios can substantially reduce GVHD in cancer patients, but pre-HSCT conditioning regimens and GVHD create a challenging inflammatory environment for Treg stability, persistence, and function. Metabolism plays a crucial role in T cell and Treg differentiation, and development of effector function. Although glycolysis is a main driver of allogeneic T cell-driven GVHD, oxidative phosphorylation is a main driver of Treg suppressor function. This review focuses on recent advances in our understanding of Treg metabolism in the context of GVHD, and discusses potential therapeutic applications of Tregs in the prevention or treatment of GVHD in cancer patients. Highlights: GVHD-mediated tissue injury induces oxidative stress and results in high metabolic demand (aerobic glycolysis, mitochondrial oxidative phosphorylation and glutaminolysis) that can reprogram naïve T cells into effector cells. Naïve thymus-derived CD4 + Tregs are highly glycolytic, where a minor proportion of energy is derived from fatty acid oxidative phosphorylation, but activated Tregs markedly increase fatty acid oxidative phosphorylation that is dependent upon mitochondrial complexes I–IV for energy and stability. Naïve CD4 + T cells can be induced in vitro or in the periphery to become Tregs. Although thymus-derived Tregs are reliant on mTOR, inhibition of mTOR can induce Treg generation, Foxp3 expression, and suppressive function. Gut microbe dysbiosis after fecal matter transplant can interfere with the production of short-chain fatty acids that support Treg generation in the gut, the major GVHD target organ.