Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation

Abstract

Galectin-8 (Gal-8) is a mammalian β-galactoside-binding lectin, endowed with proinflammatory properties. Given its capacity to enhance antigen-specific immune responses in vivo, we investigated whether Gal-8 was also able to promote APC activation to sustain T cell activation after priming. Both endogenous [dendritic cells (DCs)] and bone marrow-derived DCs (BMDCs) treated with exogenous Gal-8 exhibited a mature phenotype characterized by increased MHC class II (MHCII), CD80, and CD86 surface expression. Moreover, Gal-8-treated BMDCs (Gal-8-BMDCs) stimulated antigen-specific T cells more efficiently than immature BMDCs (iBMDCs). Proinflammatory cytokines IL-3, IL-2, IL-6, TNF, MCP-1, and MCP-5, as well as growth factor G-CSF, were augmented in Gal-8-BMDC conditioned media, with IL-6 as the most prominent. Remarkably, BMDCs from Gal-8-deficient mice ( BMDC) displayed reduced CD86 and IL-6 expression and an impaired ability to promote antigen-specific CD4 T cell activation. To test if Gal-8-induced activation correlates with the elicitation of an effective immune response, soluble Gal-8 was coadministrated with antigen during immunization of BALB/cJ mice in the experimental foot-and-mouth disease virus (FMDV) model. When a single dose of Gal-8 was added to the antigen formulation, an increased specific and neutralizing humoral response was developed, sufficient to enhance animal protection upon viral challenge. IL-6 and IFN-γ, as well as lymphoproliferative responses, were also incremented in Gal-8/antigen-immunized animals only at 48 h after immunization, suggesting that Gal-8 induces the elicitation of an inflammatory response at an early stage. Taking together, these findings argue in favor of the use of Gal-8 as an immune-stimulator molecule to enhance the adaptive immune response.

Interleukin‐6 signalling mediates Galectin‐8 co‐stimulatory activity of antigen‐specific CD4 T‐cell response

“…These findings are in agreement with our previous observations where both MHCII int CD11b high and MHC high CD11b int BMDC subpopulations, which resemble cDC and monocyte‐derived macrophages respectively, produce IL‐6 in response to Gal‐8 stimulation. Moreover, IL‐6 secretion was impaired in BMDC differentiated from Gal‐8 knockout (Gal‐8KO) mice, suggesting a physiological role for endogenous Gal‐8 in the regulation of IL‐6 production . Regarding B cells, and also in line with our findings, Tsai et al .…”

“…In summary, the in vitro model used throughout this work allowed us to show the participation of IL‐6 signalling in Gal‐8‐induced co‐stimulation during the elicitation of the antigen‐specific CD4 T‐cell response. As IL‐6 is a key cytokine involved in the differentiation of Tfh cells and germinal centre formation, our findings support a plausible mechanism by which Gal‐8 stimulates the antigen‐specific protective humoral response previously observed in a viral vaccine model . Interestingly, aged CD4 T cells require higher levels of IL‐6 produced during the CD4 T cell : APC cognate interaction compared with young CD4 T cells, to effectively induce IL‐6 signalling, read out as IgG antibody production .…”

“…Several studies positioned galectins as cue mediators of the immune response because they are implicated in many different processes such as tumour escape, autoimmune disorders, tolerance induction and host defence . Our group previously demonstrated that galectin‐8 (Gal‐8) has a predominant activating role in the elicitation of primary adaptive immune response . We found that Gal‐8 co‐stimulates borderline antigen‐specific T‐cell responses by synergizing the T‐cell receptor (TCR) ‐specific signalling in the presence of a low dose of the antigen.…”

“…In line with this, we have recently reported that Gal‐8 induces full activation of mouse bone‐marrow‐derived dendritic cells (BMDC) and splenic dendritic cells (DC), which may represent one of the mechanisms involved in the elicitation of the adaptive immune response previously observed. Indeed, Gal‐8‐stimulated DC showed increased expression of major histocompatibility complex class II (MHCII), CD80 and CD86 molecules, an augmented capacity to activate antigen‐specific T‐cell responses, and a strong production of interleukin‐6 (IL‐6), among other inflammatory cytokines …”

Molecular Mechanisms Underlying the Role of Galectin-8 as a Regulator of Cancer Growth and Metastasis

“…(GRO-γ) and CXCL8 (IL-8), in a process that requires activation of NFkB (112). Gal-8 also increases secretion of a number of chemokines and cytokines (i.e., IL-3, IL-2, IL-6, TNF-α, MCP-1, and MCP-5) from bone marrow-derived dendritic cells (113). Most relevant are the observations that increased circulating Gal-8 in (Fig.…”