CD40 ligand-expressing T helper cells induce networks of tunneling nanotubes in dendritic cells activated by mediators of type-1 immunity (IRC5P.463)

The ability of DC to mediate CD4+ T cell help for initiating cellular immunity greatly depends on instructive signals that they receive during maturation. Here we report that, in addition to producing high levels of IL-12p70, DC matured in the presence of type-1 associated inflammatory factors were also uniquely programmed to ‘reticulate’, or develop networks of tunneling nanotube-like structures in response to the CD4+ T helper cell derived signal, CD40L. Using high resolution live-cell imaging techniques, we demonstrated that tunneling nanotube networks are capable of facilitating the direct intercellular trafficking of endosome-associated vesicles, antigens, and HIV-1-like particles. Importantly, DC matured under non-type-1 polarizing conditions, such as those exposed to prostaglandin E2, failed to develop these membrane extensions. Moreover, we found that the T helper 1 associated cytokine IFN-γ plays a critical role in enhancing DC reticulation, while the T helper 2 cytokine IL-4 has a substantial inhibitory effect on this process. These data indicate that subsets of T helper cells have divergent abilities to modulate DC reticulation and subsequent intercellular communication. The induction of the reticulation process in DC represents a novel immunologic helper function of CD40L-expressing T cells, which can also be exploited by pathogens such as HIV-1 to promote direct cell-to-cell spread.