A loss of the cytosolic branched-chain aminotransferase (BCATc) facilitates Th1-like regulatory T cell generation in vitro.

Branched chain amino acids are essential for T cell proliferation and function. Their breakdown by the cytosolic branched chain aminotransferase (BCATc) negatively impacts T cell activation suggesting BCATc exerts immunosuppressive properties. Regulatory T cells (Tregs) maintain self-tolerance. The objective of this study was to explore the role of BCATc in the differentiation of CD4⁺ T cells to Tregs. Naïve CD4⁺ T cells were isolated from spleens of WT mice or mice with T cells deficient in BCATc (T-BCATcKO) and activated with anti-CD3/anti-CD28 with or without TGFβ, IL2, anti-IFNγ and anti-IL4 for 4 days to induce Treg lineage commitment (WT-iTregs or T-BCATcKO-iTregs, respectively). RT-PCR and ELISA were used to analyze the expression of BCATc and lineage specific transcription factors, Foxp3, TGFβ, T-bet, as well as the secretion of IL10, respectively. WT-iTregs significantly downregulated BCATc by 29% when compared to undifferentiated WT T cells. T-BCATcKO-iTregs significantly increased Foxp3 expression (53%), TGFβ expression (22%) and IL10 secretion (26%), while simultaneously increasing T-bet expression (109%). Pharmacological treatment of T-BCATcKO-iTregs with n-acetyl leucine amide (NALA), a leucine antagonist, significantly reversed Foxp3 and T-bet expression, and failed to upregulate IL10 secretion to the levels in control iTregs. Therefore, a loss of BCATc may generate Th1-like Treg cells and point to its regulatory role in the differentiation of CD4⁺ T cells.