The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF

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Bromodomain-containing proteins bind acetylated lysine residues on histone tails and are involved in the recruitment of additional factors that mediate histone modifications and enable transcription. A compound, I-BET-762, that inhibits binding of an acetylated histone peptide to proteins of the bromodomain and extra-terminal domain (BET) family, was previously shown to suppress the production of proinflammatory proteins by macrophages and block acute inflammation in mice. Here, we investigated the effect of short-term treatment with I-BET-762 on T-cell function. Treatment of naïve CD4 + T cells with I-BET-762 during the first 2 d of differentiation had long-lasting effects on subsequent gene expression and cytokine production. Gene expression analysis revealed up-regulated expression of several antiinflammatory gene products, including IL-10, Lag3, and Egr2, and down-regulated expression of several proinflammatory cytokines including GM-CSF and IL-17. The short 2-d treatment with I-BET-762 inhibited the ability of antigen-specific T cells, differentiated under Th1 but not Th17 conditions in vitro, to induce pathogenesis in an adoptive transfer model of experimental autoimmune encephalomyelitis. The suppressive effects of I-BET-762 on T-cell mediated inflammation in vivo were accompanied by decreased recruitment of macrophages, consistent with decreased GM-CSF production by CNS-infiltrating T cells. These effects were mimicked by an inhibitor of c-myc function, implicating reduced expression of c-myc and GM-CSF as one avenue by which I-BET-762 suppresses the inflammatory functions of T cells. Our study demonstrates that inhibiting the functions of BET-family proteins during early T-cell differentiation causes long-lasting suppression of the proinflammatory functions of Th1 cells.A promising approach for limiting production of proinflammatory molecules by T cells for treatment of autoimmune disorders has been to target enzymes that facilitate the addition or removal of epigenetic modifications. An additional level of gene regulation derives from proteins that "read" histone and DNA modifications, such as bromodomain-containing proteins that bind acetylated histones. Specifically, BRD2, BRD3, and BRD4-members of the bromodomain and extra-terminal domain (BET) family-contain two tandem N-terminal bromodomains and an extraterminal domain that has been demonstrated to bind a number of chromatin-modifying proteins. The BET family member, BRD4 has a unique C-terminal domain that binds to the positive transcription elongation factor b (P-TEFb; composed of the cyclin-dependent kinase CDK9 and its partner, cyclin T1) complex. BRD4 recruits P-TEFb to acetylated histones, promoting phosphorylation of paused RNA polymerase II (Pol II) and the repressive complexes DSIF and NELF by CDK9, thereby allowing productive mRNA elongation (reviewed in refs. 1 and 2).Given the pivotal role of BET proteins in transcriptional regulation, small molecule compounds that inhibit binding of acetylated histones to bromodomains of BET proteins ...

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Selective inhibition of CD4 ⁺ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors

Bandukwala

Gagnon

Togher

et al. 2012

174

180

“…Those mAbs that potently neutralize the biological activity of GM-CSF may be useful in treating inflammatory diseases (45) like arthritis (46) and multiple sclerosis (47)(48)(49). Anti-GM-CSF mAbs may treat juvenile myelomonocytic leukemias (50) and epithelial cancers, which secrete GM-CSF that suppresses the immune response against cancer (51,52).…”

Section: Discussionmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.

“…Similarly, in EAE, PD-1 signaling in CNS-specific helper T cells may inhibit their expansion and secretion of inflammatory cytokines (10)(11)(12). Recently, T-helper 17 (Th17) cells were shown to be involved in EAE by producing IL-17 and GM-CSF (20,21). Two reports showed that PD-1 −/− mice mount an augmented Th17 response to EAE induction (14,16).…”

mentioning

confidence: 99%

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

Rui

Honjo

Chikuma

2013

Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1 −/− ) develop spontaneous autoimmune diseases. PD-1 −/− mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1 −/− mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1 −/− recombination activating gene (RAG)2 −/− mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1 +/+ RAG2 −/− mice. This result suggested PD-1's involvement in the regulation of innate immune responses. Mice reconstituted with PD-1 −/− RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells developed more severe EAE compared with the ones reconstituted with PD-1 +/+ RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells. We found that upon recognition of HKMTB, CD11b + macrophages from PD-1 −/− mice produced very high levels of IL-6, which helped promote naive CD4 + T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells.autoimmunity | inflammation