Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS-STING Pathway.

The development of new immunomodulatory agents can impact various areas of medicine. In particular, compounds with the ability to modulate innate immunological pathways hold significant unexplored potential. Herein, we report a modular synthetic approach to the macrodiolide natural product (-)-vermiculine, an agent previously shown to possess diverse biological effects, including cytotoxic and immunosuppressive activity.

CD46 activation induces distinct CXCL-10 response in monocytes and monocyte-derived dendritic cells.

CD46 is an important immune regulatory receptor with dual functions, however, the CD46 isoform distribution and the effect of CD46 activation on the cytokine production in monocytes and monocyte-derived dendritic cells (moDCs) is unclear. Here, we show that CD46 activation of moDCs downregulates LPS-induced CXCL-10 expression, while the expression of CXCL-10 in monocytes is unaffected. Furthermore, the differentiation of moDCs induces a switch towards dominance of CYT-2 isoforms of CD46.

CD46 is a potent co-stimulatory receptor for expansion of human IFN-γ-producing CD8 T cells.

Similar to CD4 T cells, precursor CD8 T cells are thought to depend on a co-stimulatory signal through CD28 for proliferation and differentiation into effector cells. CD46 is another co-stimulatory receptor that promotes differentiation of CD4 T-helper cells type 1 (Th1 cells) into a regulatory phenotype with a switch from IFN-γ towards IL-10-secretion over time. Whether CD46 exerts a similar function on CD8 T cells remains to be fully elucidated.

Divergent tropism of HHV-6A and HHV-6B in T cells expressing different CD46 isoform patterns.

CD46 is a receptor for HHV-6A, but its role as a receptor for HHV-6B is controversial. The significance of CD46 isoforms for HHV-6A and HHV-6B tropism is unknown. HHV-6A was able to initiate transcription of the viral genes U7 and U23 in the CD46CD134 T-cell lines Peer, Jurkat, Molt3, and SupT1, whereas HHV-6B was only able to do so in Molt3 and SupT1, which expressed a CD46 isoform pattern different from Peer and Jurkat.