A loss of branched-chain aminotransferase (BCAT) enzyme function enhances T regulatory cell lineage commitment
Location
E4117 and E4119
Document Type
Presentation
Start Date
30-11-2023 2:00 PM
End Date
30-11-2023 3:00 PM
Description
Abstract
Amino acid availability strengthens T cell-driven immunity. The branched-chain amino acids (BCAAs) are essential for T cell activation. The cytosolic and mitochondrial branched-chain aminotransferases (BCATc and BCATm), which catabolize BCAAs, are implicated as T cell immunosuppressive enzymes. While BCAT enzymes are well characterized in tumor growth, their impact on CD4+ T cell lineage commitment remains unknown. The objective of this study was to decipher the role of BCATc and BCATm in the differentiation of CD4+ T cells into regulatory T cells (Tregs), which are known to maintain peripheral immunotolerance. CD4+ T cells were isolated from the spleens of wild type (WT) mice or mice with T cells deficient in BCATc (T-BCATcKO) or BCATm (T-BCATmKO) followed by activation with anti-CD3/CD28 in the absence (undifferenced control) or the presence of transforming growth factor (TGF ), cytokine-IL2, anti-IFNy and anti-IL4 for 4 days to induce Treg lineage commitment. RT-PCR was performed to analyze expression levels of the Treg lineage specific transcription factors: forkhead box protein 3 (FOXp3) and TGF . WT CD4+ T cells, induced to Tregs, significantly downregulated BCATc and BCATm. Further, a loss of expression of BCATc or BCATm significantly increased Foxp3 and TGF expression in Tregs compared to undifferenced controls. Pharmacological treatment with n-acetyl leucine amide (NALA), an antagonist of the BCAA, leucine, reversed the effect of a loss of function of BCAT. Taken together, these results indicate a loss of BCAT enzymes enhances Treg differentiation and point toward a role of BCAA metabolism in the regulation of immunotolerance.
Recommended Citation
Wetzel, Tanner and Ananieva, Elitsa, "A loss of branched-chain aminotransferase (BCAT) enzyme function enhances T regulatory cell lineage commitment" (2023). DMU Research Symposium. 4.
https://digitalcommons.dmu.edu/researchsymposium/2023rs/2023abstracts/4
A loss of branched-chain aminotransferase (BCAT) enzyme function enhances T regulatory cell lineage commitment
E4117 and E4119
Abstract
Amino acid availability strengthens T cell-driven immunity. The branched-chain amino acids (BCAAs) are essential for T cell activation. The cytosolic and mitochondrial branched-chain aminotransferases (BCATc and BCATm), which catabolize BCAAs, are implicated as T cell immunosuppressive enzymes. While BCAT enzymes are well characterized in tumor growth, their impact on CD4+ T cell lineage commitment remains unknown. The objective of this study was to decipher the role of BCATc and BCATm in the differentiation of CD4+ T cells into regulatory T cells (Tregs), which are known to maintain peripheral immunotolerance. CD4+ T cells were isolated from the spleens of wild type (WT) mice or mice with T cells deficient in BCATc (T-BCATcKO) or BCATm (T-BCATmKO) followed by activation with anti-CD3/CD28 in the absence (undifferenced control) or the presence of transforming growth factor (TGF ), cytokine-IL2, anti-IFNy and anti-IL4 for 4 days to induce Treg lineage commitment. RT-PCR was performed to analyze expression levels of the Treg lineage specific transcription factors: forkhead box protein 3 (FOXp3) and TGF . WT CD4+ T cells, induced to Tregs, significantly downregulated BCATc and BCATm. Further, a loss of expression of BCATc or BCATm significantly increased Foxp3 and TGF expression in Tregs compared to undifferenced controls. Pharmacological treatment with n-acetyl leucine amide (NALA), an antagonist of the BCAA, leucine, reversed the effect of a loss of function of BCAT. Taken together, these results indicate a loss of BCAT enzymes enhances Treg differentiation and point toward a role of BCAA metabolism in the regulation of immunotolerance.
