IL-17 Induction by ArtinM is Due to Stimulation of IL-23 and IL-1 Release and/or Interaction with CD3 in CD4+ T Cells

Abstract

ArtinM is a D-mannose-binding lectin extracted from the seeds of Artocarpus heterophyllus that interacts with TLR2 N-glycans and activates antigen-presenting cells (APCs), as manifested by IL-12 production. In vivo ArtinM administration induces Th1 immunity and confers protection against infection with several intracellular pathogens. In the murine model of Candida albicans infection, it was verified that, in addition to Th1, ArtinM induces Th17 immunity manifested by high IL-17 levels in the treated animals. Herein, we investigated the mechanisms accounting for the ArtinM-induced IL-17 production. We found that ArtinM stimulates the IL-17 production by spleen cells in BALB/c or C57BL/6 mice, a response that was significantly reduced in the absence of IL-23, MyD88, or IL-1R. Furthermore, we showed that ArtinM directly induced the IL-23 mRNA expression and the IL-1 production by macrophages. Consistently, in cell suspensions depleted of macrophages, the IL-17 production stimulated by ArtinM was reduced by 53% and the exogenous IL-23 acted synergistically with ArtinM in promoting IL-17 production by spleen cell suspensions. We verified that the absence of IL-23, IL-1R, or MyD88 inhibited, but did not block, the IL-17 production by ArtinM-stimulated spleen cells. Therefore, we investigated whether ArtinM exerts a direct effect on CD4+ T cells in promoting IL-17 production. Indeed, spleen cell suspensions depleted of CD4+ T cells responded to ArtinM with very low levels of IL-17 release. Likewise, isolated CD4+ T cells under ArtinM stimulus augmented the expression of TGF-β mRNA and released high levels of IL-17. Considering the observed synergism between IL-23 and ArtinM, we used cells from IL-23 KO mice to assess the direct effect of lectin on CD4+ T cells. We verified that ArtinM increased the IL-17 production significantly, a response that was inhibited when the CD4+ T cells were pre-incubated with anti-CD3 antibody. In conclusion, ArtinM stimulates the production of IL-17 by CD4+ T cells in two major ways: (I) through the induction of IL-23 and IL-1 by APCs and (II) through the direct interaction with CD3 on the CD4+ T cells. This study contributes to elucidation of mechanisms accounting for the property of ArtinM in inducing Th17 immunity and opens new perspectives in designing strategies for modulating immunity by using carbohydrate recognition agents.

Developmental endothelial locus‐1 (Del‐1) antagonizes Interleukin‐17‐mediated allergic asthma

“…33 Combinations of IL-1b plus IL-6 or IL-1b plus IL-23 were proposed to be the differentiation factors for human IL-17-secreting cells. 34,35 In this study, we detected a decrease in IL-23, IL-21 and IL-1b after treatment with Del-1. These results further suggest that Del-1 may inhibit IL-17 function in the development of allergic asthma.…”

ArtinM Mediates Murine T Cell Activation and Induces Cell Death in Jurkat Human Leukemic T Cells

“…We previously reported that the ArtinM-induced activation of CD4 + T cells depends on its interaction with CD3. We based this statement on our findings that ArtinM significantly reduced the labeling of CD4 + T cells with the anti-CD3 antibody, and the anti-CD3 antibody blocked the effects of ArtinM on IL-2- and IL-17-production by CD4 + T cells [ 24 , 37 ]. Similar procedures were adopted in the current work to study CD8 + T cells.…”

“…We demonstrated previously that ArtinM has a lymphoproliferative property toward murine spleen cells [ 24 ] and induces IL-17 production by CD4 + T cells [ 37 ]. These findings supported the present investigation on the effects of ArtinM on different T cell populations.…”

“…The notion that immunomodulation by ArtinM is exclusively due to its interaction with innate immune cells has changed after the description of its ability to activate T lymphocytes directly [ 24 ]. Besides inducing lymphoproliferation and IL-2 production [ 24 ], ArtinM promotes IL-17 release by acting directly on CD4 + T cells through an interaction with CD3 [ 37 ]. We designed the present study to further investigate the effects of ArtinM on murine T cells and search for new mechanisms accounting for the Th1-inducing property of lectins.…”

The lectin ArtinM activates RBL-2H3 mast cells without inducing degranulation

“…ArtinM binds directly to TLR2 N-glycans on macrophages inducing the production of cytokines such as IL-12 and IL-23, which drive the immune response to Th1 and Th17 axis and favor protection against fungal infections [45]. ArtinM also has a direct effect on CD4+ T cells, stimulating IL-17 production [46]. Activation of murine CD4⁺ and CD8⁺ T cells by ArtinM result in increased release of IL-2 and IFN-γ [47].…”