The immunoregulatory effect of the TREM2-agonist Sulfavant A in human allogeneic mixed lymphocyte reaction

Abstract

IntroductionSulfavant A (SULF A) is a synthetic derivative of naturally occurring sulfolipids. The molecule triggers TREM2-related maturation of dendritic cells (DCs) and has shown promising adjuvant activity in a cancer vaccine model.Methodsthe immunomodulatory activity of SULF A is tested in an allogeneic mixed lymphocyte reaction (MLR) assay based on monocyte-derived dendritic cells and naïve T lymphocytes from human donors. Flow cytometry multiparametric analyses and ELISA assays were performed to characterize the immune populations, T cell proliferation, and to quantify key cytokines.ResultsSupplementation of 10 µg/mL SULF A to the co-cultures induced DCs to expose the costimulatory molecules ICOSL and OX40L and to reduce release of the pro-inflammatory cytokine IL-12. After 7 days of SULF A treatment, T lymphocytes proliferated more and showed increased IL-4 synthesis along with downregulation of Th1 signals such as IFNγ, T-bet and CXCR3. Consistent with these findings, naïve T cells polarized toward a regulatory phenotype with up-regulation of FOXP3 expression and IL-10 synthesis. Flow cytometry analysis also supported the priming of a CD127-/CD4+/CD25+ subpopulation positive for ICOS, the inhibitory molecule CTLA-4, and the activation marker CD69.DiscussionThese results prove that SULF A can modulate DC-T cell synapse and stimulate lymphocyte proliferation and activation. In the hyperresponsive and uncontrolled context of the allogeneic MLR, the effect is associated to differentiation of regulatory T cell subsets and dampening of inflammatory signals.

BODIPY-Based Analogue of the TREM2-Binding Molecular Adjuvant Sulfavant A, a Chemical Tool for Imaging and Tracking Biological Systems

“…Before the introduction of 5 on the secondary glycerol position, oxidation by hydrogen peroxide gave the corresponding 6′-sulfonate 14 . Direct condensation of this product with Me 4 -BODIPY-11-undecanoic acid ( 5 ) in the presence of DCC gave 15 that was immediately deacetylated by monohydrate hydrazine − ,, to the fluorescent PB-SULF A ( 4 ). The NMR data of the product confirmed the presence of the organoboron dye linked to the glycoglycerol moiety of SULF A.…”

“…Inspired by natural immunomodulant α-6′-sulfoquinovosyldiacylglycerols (α-SQDGs), we synthesized three different non-natural β-6′-sulfoquinovosyldistearoylglycerol derivatives 1 – 3 , as new class of molecular adjuvants, collectively named Sulfavants (Figure ). − …”

“…These biological outcomes were promoted by interaction with triggering receptor expressed on myeloid cells 2 (TREM2), a specific transmembrane immunoglobulin (Ig) receptor widely present on myeloid cells (i.e., microglia, DCs, and macrophages) and essential for cell fitness and activation by a partially elusive mechanism. − Overall, TREM2-mediated effects of Sulfavants resulted in induction of an unconventional hDC maturation, determining an enhanced patrol activity with up-regulation of the costimulatory molecules without production of conventional inflammatory cytokines. This novel cell regulatory function, contributing to immune homeostasis and preserving lymphocyte activation and immune response, was pivotal for the control of the immune system in pathophysiological contexts, including inflammation, immune disorders, and cancer. , …”

H3K4me3‐Mediated FOXJ2/SLAMF8 Axis Aggravates Thrombosis and Inflammation in β2GPI/Anti‐β2GPI‐Treated Monocytes

“…FOXJ2 plays a crucial role in regulating the expression of immune response‐related genes through recognizing type A and B DNA sequences. [ 31 , 32 ] Type A sequences possess a core element that also exists in other forkhead factors, whereas type B sequences do not hold this core element. The frequency of type B sequences was lower than that of type A sequences in the site selection experiments; however, type A and B sequences have comparable affinities for fork head homologous X (FHX) sites.…”