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SATB1 prevents immune cell infiltration by regulating chromatin organization and gene expression of a chemokine gene cluster in T cells

ABSTRACT: The precise regulation of T lymphocyte development and functions is crucial for preventing the initiation and progression of autoimmunity. SATB1, a key regulator of T cell development, governs lineage-specific transcriptional programs. However, its role in autoimmunity remains unclear. Here we show that conditional knockout of Satb1 in CD4+ T cells in mice led to T cell hyperactivation and inflammatory cell infiltration in the lungs and stomach. By performing transcriptome profiling, we show that the loss of SATB1 led to the aberrant upregulation of chemokines, particularly the ones belonging to the CC subfamily. Treating Satb1 conditional knockout mice with the inhibitor of the CC chemokine receptor alleviated inflammatory cell infiltration and autoimmune phenotypes. Intriguingly, SATB1's transcriptional regulation of chemokine genes could not be attributed to its direct binding to chemokine promoters or modulation of H3K27Ac. Instead, SATB1 exerted its regulatory effects through the control of higher-order chromatin organization at the CC chemokine locus. The loss of SATB1 led to the emergence of a new chromatin domain encompassing the Ccl3, Ccl4, Ccl5, Ccl6, and Ccl9 genes and a distal enhancer, resulting in increased contacts between the enhancer and all five chemokine genes, thus inducing their upregulation. Collectively, these results demonstrate that SATB1 safeguards organisms against autoimmunity by ensuring proper chemokine expression and preventing inflammatory cell infiltration, providing valuable insights into the understanding of autoimmune diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE224977 | GEO | 2024/09/25

REPOSITORIES: GEO

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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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SATB1 prevents immune cell infiltration by regulating chromatin organization and gene expression of a chemokine gene cluster in T cells

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