Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors.
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.
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Hozefa S
HS
Bandukwala
John
J
Gagnon
Susan
S
Togher
Jason A
JA
Greenbaum
Edward D
ED
Lamperti
Nigel J
NJ
Parr
Amy M H
AM
Molesworth
Nicholas
N
Smithers
Kevin
K
Lee
Jason
J
Witherington
David F
DF
Tough
Rab K
RK
Prinjha
Bjoern
B
Peters
Anjana
A
Rao
D019264:Adoptive Transfer; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009687:Nuclear Proteins / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055291:Salivary alpha-Amylases / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology*; D000092468:Bromodomain Containing Proteins
D001569:Benzodiazepines; D016207:Cytokines; D006657:Histones; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D055291:Salivary alpha-Amylases; D013844:Thiazoles; D014157:Transcription Factors; C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C554645:molibresib; C524799:Amy1 protein, mouse