Acetyl-CoA carboxylase 1 inhibition increases Treg metabolism and graft-versus-host disease treatment efficacy via mitochondrial fusion
Cameron McDonald-Hyman, Ethan G. Aguilar, Ewoud B. Compeer, Michael C. Zaiken, Stephanie Y. Rhee, Fathima A. Mohamed, Jemma H. Larson, Michael L. Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L. Sleeth, Kyle D. Smith, Jennifer S. Whangbo, Jerome Ritz, Tim D. Sparwasser, Roddy S. O’Connor, Peter A. Crawford, Jeffrey C. Rathmell, Leslie S. Kean, Robert Zeiser, Keli L. Hippen, Michael L. Dustin, Bruce R. Blazar
Cameron McDonald-Hyman, Ethan G. Aguilar, Ewoud B. Compeer, Michael C. Zaiken, Stephanie Y. Rhee, Fathima A. Mohamed, Jemma H. Larson, Michael L. Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L. Sleeth, Kyle D. Smith, Jennifer S. Whangbo, Jerome Ritz, Tim D. Sparwasser, Roddy S. O’Connor, Peter A. Crawford, Jeffrey C. Rathmell, Leslie S. Kean, Robert Zeiser, Keli L. Hippen, Michael L. Dustin, Bruce R. Blazar
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Research Article Immunology Metabolism

Acetyl-CoA carboxylase 1 inhibition increases Treg metabolism and graft-versus-host disease treatment efficacy via mitochondrial fusion

Abstract

Tregs are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Tregs predominantly depend on oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg “effector” differentiation, but FAO activity is inhibited by coordinated activity of the isoenzymes acetyl-CoA carboxylase-1 and -2 (ACC1 and ACC2). Here, we show that small-molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic graft-versus-host disease. ACC1 inhibition skewed Tregs toward an “effector” phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to that seen with ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg-suppressive potency. Ex vivo–expanded, ACC1 inhibitor–treated human Tregs similarly augmented suppressor function, as observed with murine Tregs. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.

Authors

Cameron McDonald-Hyman, Ethan G. Aguilar, Ewoud B. Compeer, Michael C. Zaiken, Stephanie Y. Rhee, Fathima A. Mohamed, Jemma H. Larson, Michael L. Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L. Sleeth, Kyle D. Smith, Jennifer S. Whangbo, Jerome Ritz, Tim D. Sparwasser, Roddy S. O’Connor, Peter A. Crawford, Jeffrey C. Rathmell, Leslie S. Kean, Robert Zeiser, Keli L. Hippen, Michael L. Dustin, Bruce R. Blazar

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Figure 1

ACC1 inhibition enhances Treg suppressive function and suppressive molecule expression.

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ACC1 inhibition enhances Treg suppressive function and suppressive molec...
(A and B) Suppression of CD4+ Tcon proliferation in in vitro Treg suppression assays by WT versus ACC1KO Tregs (A) and DMSO- versus ND630-pretreated Tregs (B); 1:1–1:12 Treg/Tcon ratios are denoted. (C–H) Flow cytometry of suppressive molecule expression on overnight-activated WT versus ACC1KO or DMSO- versus ND630-pretreated Tregs. (C–E) Expression of TIGIT (C), Lag3 (D), and IL-10 (E) on Tregs, as evaluated by median fluorescence intensity (MFI). (F and G) Frequency of TIGIT+ (F), T-bet+, and TIGIT+T-bet+ double-positive (G) Tregs within the CD4+CD25+Foxp3+ population. (H) Expression of CD25 on CD4+Foxp3+ cells. (I) Suppression of CD4+ Tcon proliferation in in vitro suppression assays by DMSO- versus ND630-pretreated Tregs, with cultures including either isotype antibodies or a combination of blocking antibodies against Lag3, TIGIT, IL-10, and IL-10 receptor. Data show 1 experiment representative of 3 independent experiments with n = 4 replicates per group. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by unpaired t test or 1-way ANOVA. Error bars represent the mean ± SEM.