Immune system police learn early and sometimes badly
Regulatory T cells, which function like immune system police, learn early in life what to protect, and that may include viruses, bacteria and tumors, researchers have shown.
Using genetically manipulated mice and technology that enables a snapshot of the repertoire of antigen receptors that determine what cells recognize, Medical College of Georgia researchers followed T cells as they spent time in the thymus then moved to the body.
They found regulatory T cells learn what to protect while in the thymus and that everything the cells learn may not be good, according to research in the August issue of Immunity.
It is widely believed that regulatory T cells only recognize endogenous body tissue so they can stop T cells that are predisposed to attacking it, says Dr. Leszek Ignatowicz, MCG immunologist and the study's corresponding author.
By examining receptors on all types of T cells before and after they leave the thymus, researchers found regulatory T cells are very diverse and able to recognize endogenous tissue and invaders, Dr. Ignatowicz says.
Unfortunately, the cells also may not learn to recognize all endogenous tissue which, along with environmental and other factors, can lead to autoimmune disease.
T cell schooling in the thymus peaks in the first six weeks of life in the mouse, which roughly translates to the first 15 years of human life. Those early lessons seem to last a lifetime and the few regulatory cells that develop later will be like the early cells, says Dr. Rafal Pacholczyk, MCG immunologist and lead author.
The findings mean, essentially from the beginning, some people may have regulatory T cells less skilled at keeping the immune system from attacking their bodies and/or too skilled at protecting invaders.
It also means one day physicians might steer early education of regulatory T cells in the thymus as a way to vaccinate children against diseases such as lupus, arthritis and type 1diabetes. Or, they might add regulatory T cells to improve the mix in people who already have some bad police.
"We need some of the regulatory cells more than others," says Dr. Ignatowicz. "We probably need more of the ones that recognize autoantigens on the pancreas and we need the ones that recognize tumors to be less frequent."
The fact that most regulatory T cells in the body come directly from the thymus, not from other circulating T cells, also was previously unknown, Dr. Pacholczyk says. "Where they come from is the main question we wanted to answer," says Dr. Ignatowicz.
It has been thought that some T cells circulating in the body might make the transformation, possibly because of what they are exposed to in the body. In fact T cells most aggressive at attacking endogenous tissue likely would be among those converting to protective regulatory cells, Dr. Ignatowicz says. "We did not find that does not happen, but it's not the major mechanism for generating regulatory cells in the body," Dr. Pacholczyk says.
All T cells are made in the bone marrow then move to the thymus as progenitor cells where they differentiate, upregulating surface receptors, which are molecules that detect different antigens. It's a brutal process – 95 percent of the cells die in the thymus primarily because they recognize body tissue – that winds down after puberty.
All T cells wear their receptors for life, like signature hats. "We decided to compare receptors on the regulatory cells in the periphery with those in the thymus," says Dr. Pacholczyk. By analyzing receptors on individual cells, they were able to follow the cells after they left the thymus and see if they changed.
Another key question was how regulatory T cells, which make up about 5 percent of the total T cell population, can control millions of roaming T cells. They found it was a simple matter of numbers: by wearing many hats, or antigen receptors, regulatory T cells can keep their eyes on a lot of different non-regulatory cells.
"The next question we will ask, which is a hot topic right now, is what antigens trigger receptors on regulatory T cells?" says Dr. Pacholczyk. "What do they recognize? We know now they are coming from the thymus but how they are being generated is still a question. We want to look into the nature of antigens those receptors recognize which will allow us to predict more how they are being developed in the thymus."
Other study authors include Dr. Hanna Ignatowicz, geneticist, and Dr. Piotr Kraj, immunologist.
The research was funded by the National Institutes of Health and the Roche Foundation
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