The adaptive immune system’s antigen-presentation business was once thought to be monopolized by dendritic cells. But now it appears that macrophages, too, have a piece of the action. Macrophages can prime T cells directly, not just indirectly.

Indirect presentation, through dendritic cell intermediaries, is known as cross-presentation. It may be less central to the priming of T-cell-dependent immune responses than was once thought. Another possibility is that macrophages are not content to simply substitute for dendritic cells. Besides practicing disintermediation, macrophages offer unique “value add.”

These possibilities were discussed April 14 in the Proceedings of the National Academy of Sciences, in an article entitled, “CD169+ macrophages are sufficient for priming of CTLs with specificities left out by cross-priming dendritic cells.”

The article was prepared by researchers at Ludwig-Maximilians-Universität München (LMU). The researchers 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 nevertheless induces a normal immune response in a mouse model system, and even in a mouse strain that lacked dendritic cells altogether. Further experiments showed that the targeted macrophages were actually able to prime a more comprehensive immune reaction than cross-presenting dendritic cells.

“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. We have now discovered that macrophages can also do this job,” said Prof. Dr. Thomas Brocker, director of LMU’s Institute of Immunology. “Not only that, in certain situations, they can be more effective than dendritic cells.”

The LMU researchers also determined that the targeted macrophages 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.

“[Our] study shows that cross-priming [dendritic cells] generate highly restricted [cytotoxic T cell] repertoires, biased to strong MHC I binding epitopes only,” wrote the authors of the PNAS article. “Furthermore, the presence of antigen in CD169+ macrophages is sufficient for generation of [cytotoxic T cells] with broader repertoires.”

Macrophages, then, not only act as a first line of defense in the innate immune system, they can also present antigens to T cells, playing a previously unknown role in the induction of adaptive immune responses. “ In contrast to cross-priming dendritic cells, [macrophages] are capable of producing and presenting all T-cell-priming epitopes we tested,” noted Brocker. “Macrophages therefore induce a complete immune response. These observations indicate that the significance of cross-presentation by dendritic cells has been overrated.”

The new 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. 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,” explained Brocker. “Our results indicate that it may make more sense to manipulate macrophages directly, because they stimulate a wider-ranging immune response.”

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