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THU0005 Immune Complexes and Complement Mediate Epigenetic Changes and Trigger TLR Signaling in CD4+ T Cells
  1. A.K. Chauhan
  1. Rheumatology, Internal Medicine, Saint Louis University, Saint Louis University, United States

Abstract

Background In human CD4+ T cells, GWAS studies have shown hypomethylation of IFN promoter region. During activation of interferon (IFN)-1 signaling multiple genome sites are hypomethylated. Procainamide and hydrazine, which inhibit DNA (cytosine-5-)-methyltransferase 1 (DNMT1), predispose individuals to drug-induced systemic lupus erythematosus (SLE). However, what triggers these changes in SLE is unknown. The uptake of immune complexes (ICs) by pDCs drives production of the type 1 IFN. IC mediated signaling in CD4+ T cells in driving such responses has never been explored. This is due to the current accepted notion that CD4+ T cells do not express Fc receptors1. We showed the FcγRIII expression on CD4+ T cells and established their role in the development of effector T cells2.

Objectives To evaluate a role for FcgRIIIa mediated co-signal in causing epigenetic changes and alter TLR signaling.

Methods We analyzed TLR signaling and Epigenetic Chromatin Modification Enzymes in human peripheral naïve CD4+CD45RA+ T cells upon ICs+C5b-9 co-stimulation and compared them to CD28. These cells were polarized using IL1b, IL-6, IL-23 and TGF-b. Proteins associations were analyzed in pull down assays.

Results In five donors analyzed, hierarchical cluster analysis showed a strong correlation among DNMT1, RBBP7, CHD4, and MBD2, which are part of deacetylases complex. CHD4 is the main component of the nucleosome-remodeling complex. A dramatic decrease (4.5 fold) was observed in co-activator associated arginine methyl transferase and nuclear receptor co-activator (NCOA6) (7.14 fold), which remodels chromatin with HAT1. A 7.37-fold increase in activating transcription factor 2 (ATF2), a CREB family transcription factor was observed. ATF2 is also a part of AP1 family, and acetylates H2B and H4 histones during DNA damage response. ATF2 activate IL-23p19 promoter. ATF2 via Jun-mediated enhanceosome assemble at IFN-β promoter and regulates its production. ATF2/c-jun is one of three transcriptional factor complexes that regulate IFN-β gene and IFN-γ production3. K(lysine) acetyl transferase 6A was increased 6-fold. It is a transcriptional co-activator of Runx1 and Runx2. Both T-bet and Runx generate pathogenic IFN-g-producing TH17 cells. In addition, we observed 6.16-fold increase in SET domain containing lysine methyltransferases (SETD)-7, a transcription activator that generates H3K4 mark. Also other SET domain proteins SET4, SET8 that generate H4K2me1 mark and SET1 that generate H3K9 were upregulated. Surprisingly, many of TLR genes, along with HMGB1, IL6, IL10, and MAPK8 were also significantly upregulated. MAPK8 plays a key role in the cell proliferation, apoptosis, and differentiation in T cells.

Conclusions A co-stimulatory signal from FcgRIIIa in CD4+ T cells induces TLR signaling and modulates DNA modification enzymes, which then play a role in the differentiation of CD4+ T cell population.

References

  1. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 2008, 8(1): 34-47.

  2. Chauhan AK, Chen C, Moore TL, DiPaolo RJ. Induced expression of FcgammaRIIIa (CD16a) on CD4+ T cells triggers generation of IFN-gammahigh subset. J Biol Chem 2015.

  3. Falvo JV, Parekh BS, Lin CH, Fraenkel E, Maniatis T. Assembly of a functional beta interferon enhanceosome is dependent on ATF-2-c-jun heterodimer orientation. Molecular and cellular biology 2000, 20(13): 4814-4825.

Disclosure of Interest None declared

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