A loss of the cytosolic branched-chain aminotransferase, BCATc, enhances Th1 differentiation and skews Tregs to acquire a Th1-like phenotype.

BACKGROUND

T-cell fate and function are profoundly shaped by microenvironmental nutrient availability. The branched-chain amino acid, leucine, is essential for T-cell function, with its uptake via the solute carrier family 7-member 5 transporter increasing upon activation. As the enzyme catalyzing the first step of leucine degradation, the cytosolic branched-chain aminotransferase (BCATc) is induced upon T-cell activation and subsequently acts as a negative regulator of T-cell activity. However, a major knowledge gap remains regarding how BCATc modulates T-cell function beyond activation, specifically within differentiated T helper cells.

METHODS

Novel T-cell conditional knockout mouse models of BCATc, and its mitochondrial isoenzyme, BCATm, were characterized and used as a source of in vitro or ovalbumin-induced CD4+ T-cell subsets in the presence of the leucine competitive antagonist, N-acetyl leucine amide (NALA). The studies were complemented by transcriptomic analysis of human T cells using the genomic platform R2.

RESULTS

Loss of BCATc enhanced TH1 phenotype as evidenced by the increased expression of T-bet and interferon-γ. Leucine, but not the BCAT isoenzymes, was critical for TH2 and TH17 function as evidenced by the severe reduction in interleukin [IL]-13 and IL-17 release in the presence of NALA. Lastly, a loss of BCATc, or its mitochondrial isozyme, BCATm, facilitated a shift of regulatory T cells (Tregs) to a TH1-like phenotype as judged by the increased populations of T-bet+Foxp3+Tregs.

CONCLUSIONS

BCATc is the dominant BCAT isoenzyme with immunoregulatory function in CD4+ T-cell subsets and targetable potential in T-cell immunity.