Download This Paper
Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.
Toll-Like Receptor 7 Agonist Imiquimod Prevents the Progression of SLE in MRL/lpr Mice via Inhibiting the Differentiation of T Follicular Helper Cells
23 Pages Posted: 27 Jun 2019
More...Abstract
Background: Previous research has recently indicated that TLR7 is able to induce CD4+ T cell anergy, which is opposite of the role it plays in innate immune cells. T follicular helper (Tfh) cells represent a new subset of CD4+ T cells that specialize in helping B cells. Increased activity of Tfh cells plays a major pathogenic role in systemic lupus erythematosus (SLE). Therefore, TLR7 ligands may be used as a manner in which to induce 'tolerance' in Tfh cells in human autoimmune diseases.
Methods: The phenotypic and functional properties of Tfh cells were determined after treatment with TLR7 ligands imiquimod in vivo and in vitro. The phenotypic and functional properties of Tfh cells were determined in BALB/c mice and MRL/lpr mice after treatment with TLR7 ligands imiquimod. Transcription factors involved Tfh differentiation were evaluated after treatment with TLR7 ligands imiquimod. Levels of antibodies including anti-dsDNA antibodies and ANA in serum were detected after treatment with imiquimod.
Findings: We were surprised to find that the number of Tfh cells and Germinal center(GC) B cells was significantly reduced after treatment with the TLR7 agonist imiquimod. Imiquimod also significantly reduced inducible costimulatory molecule (ICOS)and programmed death 1 (PD-1) expression in Tfh cells and decreased IL-21 secretion. Moreover, imiquimod significantly reduced the gene expression of several transcription factors, including Bcl-6, c-Maf, Batf3, Nfatc2 and Stat3, but it enhanced Prdm1 and Stat5b in CD4+ T cells. Imiquimod also ameliorated the progression of SLE in MRL/lpr mice by inhibiting antidsDNA antibodies and antinuclear antibody (ANA) secretion into the serum.
Interpretation: Our results shown that TLR7 ligands imiquimod prevent the progression of SLE in MRL/lpr mice via inhibiting the differentiation of Tfh cells. Here we found that TLR7 inhibited Tfh cell development dependent on many transcription factors aside from Bcl-6. Our results demonstrated that a TLR7 agonist has the potential to be used to inhibit Tfh cell responses during SLE.
Funding Statement: This work was supported by National Natural Science Foundation of China (No. 81560504 grant to Dr Su, No. 81860138 grant to Dr Wu); Ningxia High School first-class Disciplines (West China first-class Disciplines Basic Medical Sciences at Ningxia Medical University, NXYLXK2017B07 grant to Dr Su).
Declaration of Interests: The authors declare no competing interests.
Ethics Approval Statement: This study was carried out in accordance with the recommendations of Chinese biomedical research ethical review requirements. The protocol was approved by the Ningxia Medical University Ethics Review Committee.
Keywords: Toll-like receptor 7, T follicular helper (Tfh) cells, SLE, MRL/lpr mice, 'immunity tolerance'
Suggested Citation: Suggested Citation