Immunometabolism (Cobham, Surrey) · 2026
A loss of the cytosolic branched-chain aminotransferase, BCATc, enhances Th1 differentiation and skews Tregs to acquire a Th1-like phenotype.
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Wetzel Tanner J, Adam Christie M, Kelm Tanner J, Kotula Anna E, Fagan Madison E, Khan Taha Z, Diehl Anthony X, Meyer Melissa A, Sanchez Jessica P, Ladle Brian H, Ananieva Elitsa A
Аннотация
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.
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.