Special Delivery Brings Fats to Immune System

Lipid Antigens Arrive by Lipoprotein Carriers

Photo by Graham Ramsay Peter van den Elzen (rear) and Michael Brenner found an intriguing convergence in the body’s delivery system for dietary fats and the procurement of lipid antigens for immune surveillance.

For years, the T cells of the immune system were thought to respond exclusively to protein antigens. To start the immune response, macrophages and dendritic cells chewed up large proteinaceous foes and loaded the peptide bits onto platters made up of MHC class I and II molecules for presentation to T cells. The pathways were well understood, and the processes became textbook examples of an adaptive immune response.

But pathogens are not pure protein—up to half the mass of a bacterium comes from fats and carbohydrates, a heaping helping too tempting for any reasonably alert immune system to pass up. So it was both unexpected and unsurprising when, in the mid-1990s, Michael Brenner, the Theodore Bevier Bayles professor of medicine, and his colleagues showed that some antigen-presenting cells display fats rather than proteins. Arrayed on CD1, a new type of serving tray distinct from MHC molecules, fat-containing antigens derived from the tuberculosis bacterium ably turned on a specialized subset of lipid-reactive T cells.

The route that peptide antigens take to MHC is well understood, but far less was known about where and how lipid antigens come to bind to CD1. Now, Brenner and his colleagues report that fat antigens find their target via an unexpected messenger. In a paper published in the Oct. 6 Nature, the researchers show that the immune system uses apolipoproteins, best known for their role as cholesterol carriers, to deliver lipid antigens to CD1.

“This work brings together two previously unrelated systems—the apolipoprotein-mediated delivery of dietary fats and the delivery of lipid antigens to the immune system,” Brenner said. This convergence has profound implications for understanding how the immune system patrols the body for lipid antigens, he added.

The recognition that lipid transport and immune activation both rely on apolipoprotein E (apoE) could change our understanding of many diseases, including atherosclerosis, said HMS professor of medicine Richard Blumberg, an immunologist who was not involved in the work. “These results indicate that a lot of what we have been observing with respect to cardiovascular disease, for example, which was viewed as resulting from abnormal serum lipid distribution, may in fact be the result of lipid mis-distribution to the immune system.”

Uncovering a Carrier
The discovery of apoE’s immune connection started with a bit of data-mining by Brenner lab research fellow Peter van den Elzen, now an instructor in pathology. Van den Elzen compiled gene chip data from multiple published studies tracking changes in gene expression during the maturation of monocytes to antigen-presenting dendritic cells. “CD1 is turned on as blood monocytes differentiate to dendritic cells, and we immediately picked out apoE as a gene of interest because it was coregulated with CD1 and was connected with lipid transport,” van den Elzen explained. “Our subsequent finding that dendritic cells made huge amounts of the protein suggested that it had to have some role in the immune system.”

Further experiments proved that several different lipid antigens could bind to serum apoE. Antigen complexed with apoE was 50 times more potent at enticing dendritic cells to turn on T cells than naked antigen without apoE. The reason for this, van den Elzen found, was twofold. First, when antigen rode along on apoE, it was rapidly taken up into the dendritic cells via receptor-mediated endocytosis. Without apoE, lipids gained access to cells only by a slower and much less efficient process of macropinocytosis, the random engulfment of extracellular material. Second, when apoE entered the cells via its receptor, that process delivered the lipid load directly to the endocytic vesicle system, the same cell compartment in which CD1 looks for antigen. Once the lipid is transferred, CD1 takes it to the cell surface, where it is available to activate neighboring T cells.

Secrete and Capture
The name of the game in the immune system is surveillance, and apoE is uniquely suited to play immune scout. ApoE secreted from dendritic cells goes out and soaks up lipid like a sponge, and then efficiently returns potential antigens to the cells. “The job of dendritic cells is to survey tissue for foreign antigens,” Brenner explained. “We are proposing a ‘secrete and recapture’ model as the way that the cells efficiently and with high sensitivity comb their local environment for lipid antigens.”

Image courtesy Peter van den Elzen

Serving up lipid antigens. The immune system enlists apoE to deliver lipid antigens from different sources to CD1 for presentation to T cells. In secretion–capture (indicated by number 1 in the square), apoE secreted by antigen-presenting dendritic cells can capture environmental antigens and ferry them back into the cell. Bystander acquisition allows infected cells such as macrophages to send out lipid antigens associated with apoE for delivery to nearby (uninfected) dendritic cells. Finally, serum lipoproteins such as VLDL can serve as a depot for lipid antigens, and may stimulate a response far away from the original source of the antigen. Some lipids (such as the tuberculosis antigen) require additional processing in lysosomes (not shown) before reaching the cell surface, but their entry on apoE follows the same initial path.

But apoE has other talents as well. Some pathogens, including the tuberculosis bacterium, evade immune detection by infecting macrophages and downregulating CD1 expression. The infected cells cannot alert the immune system because they fail to present antigens. In a stunning experiment, van den Elzen and immunology graduate student Luis Leon showed that apoE could carry tuberculosis antigen from infected CD1-lacking macrophages to nearby uninfected CD1-positive cells. In addition to this kind of short-distance aid, apoE, in the form of circulating very-low--density lipoprotein, might also enable immune responses to range far from the original antigen source.

With the recognition of its dual personality, apoE may find itself dragged into diverse disease scenarios beyond atherosclerosis. “This may change the way we look at activation of T cells in asthma,” said Dale Umetsu of Children’s Hospital Boston, whose work has implicated lipid-reactive T cells in asthma and allergy in both mice and humans.

Other CD1-linked diseases run the gamut from diabetes and cancer to multiple sclerosis, and each of these may have its own lipid antigens and perhaps other apolipoprotein carriers. But for Brenner the immunologist, the neatest part of the story may be the immune system’s adroitness at coopting cell housekeeping pathways for its own surveillance purposes. Like the way that MHC molecules collect the peptide products of protein degradation, CD1 picks up lipids piggybacked on incoming apoE. “If we think of the MHC proteins as the immune system’s way of searching the trash, then the CD1 proteins are its way of keeping an eye on the mail,” Brenner said. The result is an integrated invader-detection scheme that would make any security firm proud.

—Pat McCaffrey

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