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Macrophages can substitute for dendritic cells as primers of T-cell-dependent immune responses, according to research published in Proceedings of the National Academy of Sciences.
The study showed that macrophages that function as a first line of defense in the innate immune system can also present antigens to T cells, a previously unknown role for macrophages in the induction of adaptive immune responses.
“It has been assumed until now that the dendritic cells are considered to be essentially the only cell type responsible for antigen presentation in the immune system,” said Dr Thomas Brocker, of Ludwig-Maximilians-Universität München in Germany.
“We have now discovered that macrophages can also do this job. Not only that, in certain situations, they can be more effective than dendritic cells.”
Dendritic cells present antigens to cytotoxic T lymphocytes (CTLs) if they have been directly infected, but they can also capture and display antigens from other cells. This type of indirect antigen presentation is referred to as cross-presentation.
“So, theoretically, dendritic cells could be responsible for the induction of all CTL-based responses, regardless of whether they are themselves infected or not,” Dr Brocker said. “But the significance of cross-presentation is hotly debated in the literature.”
Dr Brocker and his team used several antigens that were specifically targeted to and processed by macrophages but could not be taken up directly by dendritic cells. They were able to demonstrate that each antigen induced a normal immune response in a mouse model system, and even in a mouse strain that lacked dendritic cells altogether.
Further experiments showed the targeted macrophages were actually able to prime a more comprehensive immune reaction than cross-presenting dendritic cells. They activated T cells specific for all antigen-binding sites (epitopes) presented, whereas cross-presentation by dendritic cells stimulates only those T cells that recognize immunodominant epitopes.
“Macrophages naturally function as filters,” Dr Brocker noted. “They gobble everything up that might be harmful to the organism. And our study shows that, in contrast to cross-priming dendritic cells, they are capable of producing and presenting all T-cell-priming epitopes we tested. Macrophages therefore induce a complete immune response. These observations indicate that the significance of cross-presentation by dendritic cells has been overrated.”
He added that these findings are relevant for the development of immunization strategies.
“Preclinical trials are already underway with vaccines that are designed to activate specific sets of dendritic cells,” Dr Brocker said. “But the weak epitopes are important for a broadly directed immune response, because they can potentially recognize mutant variants of viruses, for instance.”
“Cross-priming dendritic cells fail to induce weakly antigenic epitopes, as our study shows. Our results indicate that it may make more sense to manipulate macrophages directly because they stimulate a wider-ranging immune response.”
