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The lysine acetyltransferase KAT6A epigenetically facilitates glucose metabolic programming and CD4+ T-cell responses in autoimmunity

ABSTRACT: Epigenetic programs are pivotal regulators of effector CD4+ T cells and determine the fate of many autoimmune disorders. Here, we show that the acetyltransferase KAT6A acts as a novel regulator of glucose metabolism that is required for the proliferation and effector functions of CD4+ T cells in autoimmunity. Clinical analysis shows that KAT6A in CD4+ T cells is linked to the progression of autoimmune Sjogren’s syndrome (SS) . Conditional knockout of KAT6A inhibits the proliferation and Th1/Th17 effector functions of CD4+ T cells both in vitro and that KAT6A-cKO CD4+T cells are less susceptible to induce adjuvant-immunized experimental autoimmune encephalomyelitis (EAE), autoimmune colitis and experimental SS. Combination of metabolomic, epigenetic and transcriptomic analyses show that KAT6A maintains abundant acetylation of H3K9ac and H3K27ac sites of several glycolytic genes, which in turn disrupts the transcriptional activation of MYC and HIF-1α, and potentiates the metabolic programming of glycolysis through its enzymatic amino acid points. Treatment with KAT6A small-molecule inhibitors in various autoimmune mice models shows high therapeutic value for targeting KAT6A to the treatment of autoimmune disorders. Our study reveals a critical role for KAT6A in autoimmunity via the epigenetic modification of glucose metabolic reprogramming and the effector response of CD4+ T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE241099 | GEO | 2023/12/09

REPOSITORIES: GEO

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Project description:This is system 2, the model with Michelis Menten type antigen uptake by pAPCs, described in the article: Self-tolerance and Autoimmunity in a Regulatory T Cell Model. Alexander HK, Wahl LM. Bull Math Biol. 2010 Mar 2. PMID: 20195912 , doi: 10.1007/s11538-010-9519-2 ; Abstract: The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R (0) for each system. When R (0) 1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the system's qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to sub-clinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach). Originally created by libAntimony v1.4 (using libSBML 3.4.1)

Project description:This is system 1, the model with linear antigen uptake by pAPCs, described in the article: Self-tolerance and Autoimmunity in a Regulatory T Cell Model. Alexander HK, Wahl LM. Bull Math Biol. 2010 Mar 2. PMID:20195912, doi:10.1007/s11538-010-9519-2; Abstract: The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R (0) for each system. When R (0) 1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the system's qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to sub-clinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach). Originally created by libAntimony v1.4 (using libSBML 3.4.1)

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The lysine acetyltransferase KAT6A epigenetically facilitates glucose metabolic programming and CD4+ T-cell responses in autoimmunity

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