by syaffolee

When Highway Robbery Pays

What is self and non-self? That question might drive philosophers and psychologists mad with hypotheses about ego, id, and the consciousness, but nature has figured out a way to distinguish us from the rest of the environment. The immune system.

Most of the time, we don’t even think about this part of ourselves unless we come down with a cold or accidentally trip and skin our knees. But our immune system is constantly on guard like the stations at a border crossing. Inspection is also a lot like what happens at those border crossings. If you want to get from Country A to Country B, you present your passport for the immigrations official to inspect. All the cells in your body have a sort of passport to identify themselves as “self”–the major histocompatibility complex (MHC). The MHC is expressed on the cell surface; the MHC itself helps present antigens. The antigen is like the photo and name on the passport. If the antigen is a self antigen, i.e. the cell’s own protein, then a passing immune cell like the T cell inspecting the MHC with its own T cell receptor (TCR) which acts like a passport scanner will let it go on its way. The TCR itself only causes the T cell to react and sound the alarm when it encounters a non-self antigen (like bacterial and viral protein).

Most of the time, this works like a charm. This is because T cells have to go to charm school before they’re let loose on the rest of the body. Charm school for T cells, however, is probably nothing like going to a finishing school in Switzerland. Immature T cells are sent to the thymus to be educated. As these T cells begin to express their receptors, the TCR is also tested for reaction with self antigen by a variety of antigen presenting cells. If the TCR binds to a protein made in your own body, the T cell that expressed that TCR would immediately get eliminated. The educators in the thymus know that it would be an extremely bad thing if the police force they’re training starts killing off their own citizens.

But sometimes it does go wrong, and as a result, we get autoimmune diseases like arthritis. There are some backup mechanisms to prevent this from happening, especially if a T cell that responds to self antigen somehow escapes the thymus. A T cell can’t be activated just by the TCR getting into contact with an antigen presenting MHC. Other receptors and ligands must also come together at the same time in a process called costimulation. Another backup plan is the Fas receptor. In the thymus, this is a mechanism to kill off the T cells that don’t come up to snuff. The eye cells also does this. If a rogue T cell wanders into the vicinity of the eye, the Fas ligand (which the eye cells express on their surface), will come in contact with the T cell Fas receptor. The result of this fatal meeting is the death of the rogue T cell.

A recent paper in Nature Immunology by Perchellet et al. describe another way in which our body establishes immune tolerance. This new mechanism, however, is quite unusual. Rather than acting as the classic border patrol official, some high-affinity T cells become Robin Hoods along the highways of the body.

The researchers used a mouse model to study multiple sclerosis, a serious autoimmune disease where the immune cells have gone haywire and have started attacking nerve cells. The problem arises when T cells start expressing a TCR that recognizes myelin–a protein that helps insulate nerve cells–escape from the selection pressures of the thymus and start proliferating. In studying the populations of immune cells in mice that make myelin and those that don’t, the researchers found a curious thing.

Normally, myelin (MBP, myelin basic protein) is only produced in the nerve cells. For educating the T cells, the thymus expresses a form of myelin called golli-MBP. Usually, this is enough to prevent any T cells that recognize myelin from getting out of the thymus. Sometimes, though, that doesn’t happen. Perchellet et al. generated T cells that respond to MBP by exposing them to a virus that was engineered to make MBP. But even without the selection pressure of the thymus, this was still not enough to generate a multiple sclerosis-like response in the mice. What was happening?

By observing the interactions of these T cells that could be activated by MBP, they found that these lower-affinity T cells were coming into contact with high-affinity T cells and the high-affinity cells are somehow stripping the other cell of their receptors without activating the lower-affinity cells or themselves. These Robin Hood cells perform the much needed backup service of preventing T cells that respond to MBP from proliferating, but they walk a very thin and dangerous line. This line of defense could easily break down–much like the Sheriff of Nottingham finally deciding to mobilize his evil henchmen.