By David N. Leff

Close encounters of the first kind transpire whenever your immune system confronts and counters an invading virus or bacterium.

"The way people envision this happening now," observed immunologist and cell biologist Michael Dustin, "is that you have, say, a reaction that's initiated in the skin. There are resident cells in the skin whose job is to pick up proteins of any kind - bacterial, viral, a lot of your own proteins. Under conditions of stress," he explained, "those antigen-presenting cells, APCs as they're called, will migrate with those antigen proteins to the nearest lymph node draining that insulted tissue."

It's there that the APC is likely to find the immune system's T lymphocytes, which are poised to eliminate such threats. But getting those two cells together involves an elaborate concatenation of events, of ultra-soap opera complexity.

Dustin is an associate professor of preclinical pathology at Washington University in St. Louis. "We're working in the immune system," he told BioWorld Today, "in particular, cell-to-cell interaction. The communication process that we're interested in is how a helper T lymphocyte communicates with an antigen-presenting cell. That's a kind of messenger cell that picks up proteins from the tissues and alters their form so that the T cell can potentially see them."

That alteration consists of mincing the whole pathogen into bite-size peptides, by means of proteolytic enzymes. Then the APC, typically a dendritic cell, parks its antigenic quarry on its surface, where the T cell has to somehow read them out, and prepare for action.

This simple-sounding setup actually is fraught with immunological puzzlement. An article in today's Science, dated July 9, 1999, of which Dustin is lead author, describes an artificial working model of that cell-cell tryst that raises a corner of the multiple conundrum. Its title: "The immunological synapse: A molecular machine controlling T cell activation."

Dustin explained: "A synapse is really a junction. What we call the immunological synapse is not from the T cell or the APC but really from both. It's a shared structure.

"The cover of the Science article," he pointed out, "shows a T cell interacting with a dendritic cell. Those cells migrate out, go to the lymph node, and there interact with hundreds if not thousands of T lymphocytes over the course of the day. These T cells are percolating through the lymph node, where the loaded dendritic cell goes in, and shows what it's got.

"The T cells passing through," he went on, "bump into the APC, may be attracted to it, and kind of scan it. And this is where the immunological synapse comes into play, because if there's no relevant antigen, the T cell will just move on. However, if there is physical interaction between these antigen molecules on the messenger and the antigen receptor on the T cell, that will initiate the T cell's process of deciding what to do next.

"In order for this process to work," he pointed out, "each dendritic cell that comes into a lymph node has to see multiple T lymphocytes. If the antigenic quality is high enough for that particular T cell's antigen receptor, then it can form this cell-membrane structure at the point of APC contact on its surface. That structure is an immunological synapse with a bull's-eye pattern. Then the T cells, once they form the synapse, get activated and start making multiple copies of themselves. Those clones have to migrate out, go back to the tissue site of the initial injury, where the bacteria have gotten in.

"The helper T cells that we're focusing on," Dustin continued, "are really the leaders of that process. Like a general in a military operation, they will recruit other cell types required to clear the infection. And if you don't have those functions, then there is obviously a wide range of pathogens that you're going to be very susceptible to. Such as immune-suppressed people with HIV infections and AIDS. You have some very specific things that absolutely require T-cell help to work, to get rid of them."

Constructing The Mechanical Synapse

Dustin and his co-authors contrived their lab-made surrogate immunological synapse to reproduce observably in real time what goes on between dendritic and T cells in the immune system.

"We used cytochrome c and hemoglobin from transgenic mice as model antigens," he said. "We've replaced the protein-cleaving step that the APC would normally do with synthetic peptides. That way, we can get much better resolution that we can from cell-cell systems. The substrate is an optically ideal set-up, giving us a really clear view of what is happening.

"Some day," Dustin mused, "the imaging technology may be good enough to deal with a cell-cell system, but that could be 10 years down the road. Meanwhile, we have a system right now where we can set up an immunological synapse, study its function and evaluate potential agents to block its formation."

Presumably sooner than 10 years from now, he foresees potential payoffs from the system. "Until now," he observed, "we were looking at T cells that were seeing antigen for the second time in their life cycle. Now we're working to activate a naove T cell, one that's never encountered its antigen before. And we're evaluating the idea that the immunological synapse forms only when you have additional molecules in the dendritic cell's bilayer membrane. One candidate would be CD80. This is now a really hot molecule, because it seems to convert nonimmunogenic tumors to immunogenic tumors.

"That molecule would sit on the APC surface only when the initial pickup of the antigen was inflammatory. So if here was a wound with some real bacteria in it, that'll change the composition of the APC surface. The T cell then reads that together with the antigen, and that contributes to its decision whether or not to go active.

"This is where autoimmune diseases come in," Dustin pointed out. "You have these T cells in your body that are reactive against your own proteins. Normally you don't activate them because, in rheumatoid arthritis, for instance, when you see collagen from your joints it's not normally under inflammatory conditions, so you don't get the immune response. Or in the brain with multiple sclerosis, the T cells see myelin basic protein, but they won't respond to it because they've seen it in noninflammatory conditions. When you can find inflammation in some manner - and this is the whole basis of autoimmune disease - you get this inappropriate response, and it becomes self-sustaining. That's a disaster."

Dustin made the point, "These molecular actions at the cell surface have been seen for some time as good targets for therapeutics. The big challenge is to come up with small molecules that block big proteins. The big pharmaceutical companies," he added, "are interested in small molecules, but the biotech companies are pushing more in cases where it seems like the expense of putting a specific protein into production needs to be balanced with the potential benefit of getting that kind of drug. There's really a niche that isn't filled by any small molecule.

"Things like that are really working out for us," Dustin concluded. "We're collaborating with Boehringer Ingelheim and with Biogen on projects to try to block those inflammatory processes by inhibiting immunological synapse formation."