GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation.

Siwen Kang, Lingling Liu, Tingting Wang, Matthew Cannon, Penghui Lin, Teresa W-M Fan, David A Scott, Hsin-Jung Joyce Wu, Andrew N Lane, Ruoning Wang

Nature metabolism 2022 Oct

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γ-Aminobutyrate (GAB), the biochemical form of (GABA) γ-aminobutyric acid, participates in shaping physiological processes, including the immune response. How GAB metabolism is controlled to mediate such functions remains elusive. Here we show that GAB is one of the most abundant metabolites in CD4+ T helper 17 (TH17) and induced T regulatory (iTreg) cells. GAB functions as a bioenergetic and signalling gatekeeper by reciprocally controlling pro-inflammatory TH17 cell and anti-inflammatory iTreg cell differentiation through distinct mechanisms. 4-Aminobutyrate aminotransferase (ABAT) funnels GAB into the tricarboxylic acid (TCA) cycle to maximize carbon allocation in promoting TH17 cell differentiation. By contrast, the absence of ABAT activity in iTreg cells enables GAB to be exported to the extracellular environment where it acts as an autocrine signalling metabolite that promotes iTreg cell differentiation. Accordingly, ablation of ABAT activity in T cells protects against experimental autoimmune encephalomyelitis (EAE) progression. Conversely, ablation of GABAA receptor in T cells worsens EAE. Our results suggest that the cell-autonomous control of GAB on CD4+ T cells is bimodal and consists of the sequential action of two processes, ABAT-dependent mitochondrial anaplerosis and the receptor-dependent signalling response, both of which are required for T cell-mediated inflammation. © 2022. The Author(s).

Citation

Siwen Kang, Lingling Liu, Tingting Wang, Matthew Cannon, Penghui Lin, Teresa W-M Fan, David A Scott, Hsin-Jung Joyce Wu, Andrew N Lane, Ruoning Wang. GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation. Nature metabolism. 2022 Oct;4(10):1322-1335