How the immune system gets where it needs to go

In honor of the great Scienceblogs migration, and inspired by Ethan's wonderful post about the migration of the universe, I thought I would talk about something on a smaller scale: cell migration.

The scale is small, but the problem is huge. Most of your organs are locked in place - your heart never needs to be in your thigh - but the immune system has to be everywhere. When you cut your toe, breathe a virus into your lungs or eat a piece of contaminated spinach, the immune system needs to be johnny-on-the-spot with the inflammatory response.

Thankfully, there's already an organ system that reaches just about every place in the body: the circulatory system. In fact, the red blood cells that carry oxygen through your blood vessels and the white blood cells that make up the immune system develop from the exact same precursor cells in the bone marrow.

A schematic of how different blood cells develop from a common stem cell

The blood vessels act as highways, rapidly moving cells around to the various locations in your body. For red blood cells, this is enough. They're able to absorb oxygen in the lungs and dump it off in tissues that need it all while staying confined within the vessel wall. And a red blood cell is a red blood cell - there are a lot of them and they need to go everywhere, but it's not important to get a particular red blood cell to a particular organ. But immune cells need to go to particular locations. It does you no good to send a macrophage to your lungs when you get a cut on your foot. In addition, immune cells can't just fly by, they actually need to exit the bloodstream and move into the tissue to carry out their function. Both of these problems - getting to the right location and getting out of the bloodstream - are solved by the same set of 3 proteins.

Let's start with the second problem: slowing down and getting out.

It's tough to appreciate in the beginning of this video, but the blood flow is astonishingly fast - those vessels are packed with red blood cells moving so fast that you can't see them. If you're still thinking of blood vessels like a highway, the problem the immune cells contend with is like trying to take an offramp while traffic is moving at a few hundred miles per hour - they need to slow down.

To accomplish this, the cells lining the blood vessels can express special proteins on their surface called "selectins," that are able to grab onto special sugars present on the immune cells. My apologies for the mixed metaphors, but you can think of this process like velcro - the immune cells are lined with the fuzzy stuff, and the blood vessel cells have the bristles that let them adhere. This interaction slows the immune cells down and allows them to roll along the vessel well, but it's not enough to bring them to a halt. For that, the immune cells deploy another type of protein: integrins.

Integrins can exist in two different shapes. When they are inactive, they are folded over, and unable to interact with anything. But when the cell receives a particular signal (which I'll get to in a minute), the integrin unfolds, and is able to latch on to specific partner protein.

The inactive integrin (left) is folded over and unable to interact with it's partner (ligand), but the active integrin (right) has an open conformation and can bind tightly

This binding between an integrin and its partner ligand (expressed on the blood vessel wall) is strong enough to fully arrest the immune cells, which can then squeeze through the gaps in between the cells that make up the walls of the blood vessel.

The final piece of the puzzle that you need to understand is what causes the activation of the integrin. Chemical signals called "chemokines" are produced by inflammed tissues, and these chemokines interact with receptors on the immune cells, telling them to extend their integrins in order to dock onto the vessel wall.

To recap: cells lining the blood vessel express selectins that bind sugars on immune cells, slowing them down and letting them roll along the vessel wall. Chemokines then signal to the immune cells that it's time to activate their integrins, which can then grab tightly to the vessel wall, allowing the cell to stop and migrate across and into the tissue.

What I haven't mentioned yet is that there are many different kinds of selectins, chemokines and integrins, and each of these different kinds have specific partners. This is the key to directing the immune response to a particular area of the body. First of all, only inflamed tissues will express the selectins necessary to get immune cells rolling. In the following video, blood vessels are black, and immune cells are white. In the vertical vessel, you can see immune cells slowing down and rolling, but if you watch carefully, you can see immune cells fly by in the two horizontal vessels, which don't have the right selectin/sugar pair*.

Selectins and migration

The same principal holds true for chemokines and integrins as well - chemokines pair with specific chemokine receptors, and integrins pair with specific integrin ligands. Imagine you're a T-cell that needs to get into the lung to do your job. You'll express selectins that look for inflammation, chemokine receptors indicative of T-cells and a lung-specific integrin. On your way through the blood stream, you pass by a cut on the toe. The toe is inflamed, so your selectins bind and you start to roll, and the toe is looking for T-cells, so they express the right chemokines to activate your integrins, but there's no ligand for your integrin. Since the integrin won't bind, you won't stop, and once you pass that area of inflammation, you'll fly through the blood vessel again looking for the right combination.

Like a telephone area code, all three units have to be right to get where you're going. In my example, the foot is San Diego (619) and the lungs are Boston (617) - two out of three parts are the same, but they take you to very different places. Using an almost endless combination of these three factors, the immune system has evolved to send the right cells to the right place, almost every time.