Minimal sequence requirements for oligodeoxyribonucleotides activating human TLR9

The Journal of Immunology : Official Journal of the American Association of Immunologists
Jelka PoharMojca Benčina

Abstract

Synthetic oligodeoxyribonucleotides (ODNs) containing CpG (unmethylated deoxycytidylyl-deoxyguanosine dinucleotide) motifs activate endosomal TLR9. The nucleotide sequence, length, and dimerization properties of ODNs modulate their activation of TLR9. We performed a systematic investigation of the sequence motifs of B-class and C-class phosphodiester ODNs to identify the sequence properties that govern TLR9 activation. ODNs shorter than 21 nt and with the adenosine adjacent to the cytidine-guanosine (CG) dinucleotide motif led to a significant loss of the propensity to activate TLR9. The distance between the stimulatory CpG motifs within the ODN fine-tunes the activation of B cells. The minimal ODNs that activate human TLR9 comprise 2 CG dinucleotides separated by 6-10 nt, where the first CpG motif is preceded by the 5'-thymidine and the elongated poly-thymidine tail at the 3' end of the ODN. The minimal sequence provides insight into the molecular mechanism of TLR9 ligand recognition. On the basis of sequence requirements, we conclude that two binding sites with different affinities for CG are formed in the human TLR9 dimer, with a very stringent binding site interacting with the 5' CpG motif.

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Citations

May 23, 2017·Nature Communications·Jelka PoharMojca Benčina
Apr 11, 2017·Immunology Letters·Nina PirherRoman Jerala
Jan 25, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jelka PoharMojca Benčina
May 14, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Anil K Chauhan
Jul 3, 2018·FEBS Letters·Hanako IshidaToshiyuki Shimizu
Sep 29, 2018·Annual Review of Virology·Zhe MaBlossom Damania
Jan 1, 2020·Current Protein & Peptide Science·Laura C García-CarneroAlma K Tamez-Castrellón
Sep 30, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jelka PoharMojca Benčina
Oct 1, 2017·Nature Ecology & Evolution·C Jessica E MetcalfAndrea L Graham
Mar 1, 2016·Biophysics Reviews·Umeharu Ohto, Toshiyuki Shimizu
Jul 9, 2016·PloS One·Vida ForstneričMojca Benčina
Apr 8, 2020·Molecular Therapy. Methods & Clinical Development·Seemin S AhmedOmar L Francone

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