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Direct ODN ligation on CD4+ T cells results in the activation of TLR9 signaling
Journal article   Peer reviewed

Direct ODN ligation on CD4+ T cells results in the activation of TLR9 signaling

Ravi Kumar Sharma, Jyoti Sharma, Ajinkya Pattekar, Pooja Jain and Naresh Sachdeva
The Journal of immunology (1950), v 198(1_Supplement), 75.19
01 May 2017
DOI: https://doi.org/10.4049/jimmunol.198.Supp.75.19

Abstract

Abstract Oligodeoxynucleotides (ODNs) are established ligands for TLR9, however functional response via ODN in CD4+ T cells has been believed to be independent of TLR9 and MyD88. Here, we studied the uptake of ODN2216 in human peripheral CD4+ T cells and assessed its effect on TLR9 signaling. We observed that ODN2216 was taken up intracellularly by endocytosis in CD4+ T cells, leading to increase in gene expression of TLR9 in a time dependent manner (p=0.029). The inhibition of endocytosis by dynasore and promethazine resulted in lower uptake of ODN2216 by CD4+ T cells. Inhibition of MyD88 resulted in decreased uptake of ODN2216 (p=0.0009) by CD4+ T cells, while there was no significant effect of inhibiting IRAK1 or IRAK4. Post uptake, we observed a significant increase in gene expression of TLR9, MyD88, IRAK1, IRF-7, and TRAF3 but unlike canonical TLR9 signaling, there was no significant increase in expression of IRAK4, IRF-3, and TRAF6 (p<0.0001). Moreover, TLR9 expression on CD4+T cells also decreased significantly upon treatment with endocytosis inhibitor (p=0.0001), MyD88 inhibitor (p=0.016), IRAK1 inhibitor (p=0.0001) but not IRAK4 inhibitor as compared with untreated CD4+ T cells. Further the uptake of ODN2216 led to an increase in TGF-β synthesis in TLR9 signaling dependent fashion by CD4+ T cells (p<0.0001). Collectively, our results demonstrate a direct but distinct TLR9 agonist ligation induced signaling pathway in CD4+ T cells which is independent of antigen presenting cells. This TLR9 signaling pathway may have a significant role in modulation of T-cell responses in exaggerated inflammatory responses.

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