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.
|Number of pages
|Published - Oct 2022
Bibliographical noteFunding Information:
This work was supported by 1U01CA232488-01 from the National Institute of Health (Cancer Moonshot program), 2R01AI114581-06 and R01CA247941 from the National Institutes of Health, V2014-001 from the V-Foundation and 128436-RSG-15-180-01-LIB from the American Cancer Society (to R.W.) and by T32 Ruth L. Kirschstein National Research Service Award CA 269052 from the National Institutes of Health (to S.K.). The Sanford Burnham Prebys Cancer Metabolism Core was supported by the SBP NVI Cancer Center Support Grant P30 CA030199 (to D.A.S.). The Center for Environmental and Systems Biochemistry Core was supported in part by the Markey Cancer Center support grant P30CA177558 (to A.N.L.).
© 2022, The Author(s).
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
- Physiology (medical)
- Cell Biology